Self-emulsifying composition of omega3 fatty acid

ABSTRACT

A self-emulsifying composition contains: 70 to 90% by weight in total of one or more compounds selected from the group consisting of ω3 polyunsaturated fatty acids and their pharmaceutically acceptable salts and esters; 1 to 29% by weight of an emulsifying agent selected from among a polyoxyethylene sorbitan fatty acid ester, a sorbitan fatty acid ester, a glycerin fatty acid ester and a polyoxyl castor oil; and 0.5 to 6% by weight of water when the composition is defined to be 100% by weight as a whole. The self-emulsifying composition is excellent in self-emulsifying property, composition dispersibility, emulsion stability, and absorbability, is free from ethanol and polyhydric alcohols or only has such an alcohol added thereto at a reduced concentration, and is useful for foods and pharmaceuticals.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a Continuation of copending application Ser. No.16/380,663, filed Apr. 10, 2019, which is a continuation of applicationSer. No. 15/684,694, filed Aug. 23, 2017, which is a Continuation ofcopending application Ser. No. 14/905,520, filed on Jan. 15, 2016, nowU.S. Pat. No. 9,801,843, which is the National Phase under 35 U.S.C. §371 of International Application No. PCT/JP2014/069115, filed on Jul.17, 2014, which claims the benefit under 35 U.S.C. § 119(a) to PatentApplication No. 2013-149645, filed in Japan on Jul. 18, 2013, all ofwhich are hereby expressly incorporated by reference into the presentapplication.

TECHNICAL FIELD

This invention provides a self-emulsifying composition containing atleast one member selected from the group consisting of ω3polyunsaturated fatty acids and their pharmaceutically acceptable saltsand esters. This invention also provides a pharmaceutical product usingsuch a composition, and production and application methods thereof.

BACKGROUND ART

Known ω3 polyunsaturated fatty acids (hereinafter abbreviated as ω3PUFA) include α-linolenic acid, eicosapentaenoic acid (hereinafterabbreviated as EPA), and docosahexaenoic acid (hereinafter abbreviatedas DHA). Since the ω3 PUFA and pharmaceutically acceptable salts andesters thereof have actions such as anti-arteriosclerosis action,platelet aggregation suppressive action, blood lipid lowering action,anti-inflammatory action, carcinostatic action, and central action, theyare blended in various food products, and commercially sold in the formof health food and medical and pharmaceutical products.

Ethyl eicosapentaenoate ester (hereinafter abbreviated as EPA-E) iscommercially sold in Japan as an oral therapeutic agent for amelioratingulcer, pain, and coldness associated with arteriosclerosis obliterans aswell as hyperlipidemia (product name Epadel, Mochida Pharmaceutical Co.,Ltd.). When EPA-E is orally administered under fasting, increase inplasma EPA concentration is smaller than the case of the oraladministration after the meal conceivably because absorption of theEPA-E requires secretion of bile acid and food components as a carrier.Accordingly, Epadel is instructed to be orally administered immediatelyafter the meal (see Non-Patent Literature 1).

However, dosage method or drug compliance has become a problem for thosepeople not taking breakfast with the recent change in the life style,patients who can only take meals at a reduced amount, patients who canonly take a fluid diet (milk, rice broth, starch gruel, egg, soup,juice, or oral nutritional supplement), patients with reduced absorptionability of the intestinal tract (for example, elderly, patients ofintestinal disease, patients after intestinal surgery, terminal cancerpatients, and patients taking a lipase inhibitor), or patients who areunable to take meals such as those after the cerebral infarction.

Recent attention is being drawn to the relationship of the conditionwhere the serum triglyceride (hereafter abbreviated as TG) level isabnormally increased after meals while being normal upon fasting, ornon-fasting hypertriglyceridemia with a prolongation of such abnormalincrease, to coronary artery disease, and it is desired to develop an ω3PUFA preparation rapidly absorbable even if administered before mealsand capable of suppressing the increase in serum TG level after meals.

A self-emulsifying preparation which does not contain water in thepreparation and which is readily dispersible and self-emulsifying whenbrought into contact with water has been reported (see Patent Literature1 and Non-Patent Literature 4). This preparation contains an ω3 PUFA andfenofibrate as its effective components, ethanol, and a surfactant.

These compositions contain ethanol as a component added for improvingthe dissolution of the fenofibrate. However, volatilization of theethanol is associated with the risk of capsule deformation and bubbleinclusion in the capsule, damages in the quality such as capsuledeformation and cracks, as well as denaturing of the content in thecapsule such as cloudiness and separation. In addition, use of apreparation containing such composition should be difficult if notimpossible for patients intolerable for the alcohol (ethanol).

A self-emulsifying composition containing ethanol and polyhydricalcohols in addition to the ω3 PUFA and a surfactant which is capable offorming a dispersion having a small or very small average particle sizewhen brought in contact with water is also reported (Patent Literature2).

With regard to self-emulsifying compositions having a low ethanolcontent, a self-emulsifying composition comprising an ω3 PUFA, anemulsifier having a hydrophile lipophile balance (hereinafterabbreviated as HLB) of at least 10, lecithin, and a polyhydric alcoholsuch as propylene glycol or glycerin which has high self-emulsifyingproperty, oral fasting absorbability and absorption speed has beenreported (Patent Literature 3).

When a composition containing a co-solvent such as a polyhydric alcoholis encapsulated in a capsule, the co-solvent moves to the capsule filmto cause denaturing of the composition as well as capsule deformationdue to the softening of the capsule (Patent Literature 4).

Self-emulsifying compositions, as generally containing larger amounts ofemulsifiers and, accordingly, being increased in total amount, areliable to cause inflammation of the gastrointestinal tract or have areduced content per capsule of the biologically active componentdissolved in oil component (Patent Literature 5). Accordingly, theemulsifier used in the self-emulsifying composition is preferably theone which is non-toxic or less-toxic even in the case of continuousadministration, and the emulsifier is preferably used at a low content.

In view of compliance, amount of the emulsifier and alcoholsincorporated should be minimized also in consideration of reducing thesize of the preparation because amount of the preparation that has to betaken per administration increases with the increase in the amount ofthe components other than the ω3 PUFA in the self-emulsifyingcomposition since predetermined amount of the ω3 PUFA should be takenper administration.

CITATION LIST Patent Literatures

Patent Literature 1: JP 2008-516890 A

Patent Literature 2: JP 2012-519728 A

Patent Literature 3: WO 2010/134614

Patent Literature 4: JP 2011-12003 A

Patent Literature 5: JP 2012-180337 A

NON-PATENT LITERATURES

Non-Patent Literature 1: Epadel S (Drug Interview Form), MochidaPharmaceutical Co., Ltd., June, 2012

Non-Patent Literature 2: “Guideline for Diagnosis and Prevention ofAtherosclerotic Cardiovascular Diseases, 2007 Edition” edited by JapanAtherosclerosis Society and published by Kyowa Kikaku Ltd., Apr. 25,2007

Non-Patent Literature 3: Diabetes, vol. 57, No. 9, 2382-2392, 2008

Non-Patent Literature 4: European Journal of Pharmaceutical Sciences,vol. 33, 351-360, 2008

Non-Patent Literature 5: “2007 Dictionary of Drug Additives” edited byInternational Pharmaceutical Excipients Council Japan and published byYakuji Nippo Ltd., Jul. 25, 2007

SUMMARY OF INVENTION Technical Problems

There is a demand for a preparation wherein ethanol and polyhydricalcohols added to the self-emulsifying composition have been reduced.

There is also a demand for a preparation wherein emulsifier added to theself-emulsifying composition has been reduced.

There is also a demand for a preparation wherein content of the ω3 PUFAin the self-emulsifying composition has been increased.

There is also a demand for a self-emulsifying composition which showsexcellent drug compliance.

There is also a demand for a self-emulsifying composition which is freefrom denaturing such as cloudiness and separation and which retains thegood appearance during its storage at room temperature, and also, at lowtemperature and high temperature environments since use of theself-emulsifying composition as a drug may involve storage in colddistrict and other environments.

There is also a demand for a self-emulsifying composition wherein thecomposition has stable quality.

There is also a demand for a preparation wherein the self-emulsifyingcomposition has been encapsulated.

There is also a demand for a preparation wherein softening of thecapsule film after the encapsulation of the self-emulsifying compositionis suppressed so that the capsulated preparation is not deformed.

Accordingly, an object of the present invention is to provide aself-emulsifying composition which has realized one or more of thedemands as described above. Another object of the present invention isto provide a preparation encapsulating such composition.

Solution to Problems

In view of the problems as described above, the inventors of the presentinvention made an intensive investigation on the components which wouldbe substitutes for the ethanol and the polyhydric alcohols, and foundthat a predetermined amount of water is useful in improving thecompatibility of the self-emulsifying composition.

The inventors also found that the content of the emulsifying agent canbe further reduced, and a self-emulsifying composition having a highcontent of the ω3 PUFA was thereby completed. The present invention hasbeen completed on the basis of such findings.

The composition of the present invention is a composition which exhibitsexcellent properties with regard to at least one of the problems asdescribed above.

Accordingly, a first aspect of the present invention is theself-emulsifying composition as described below.

(1-1) A self-emulsifying composition comprising, when theself-emulsifying composition is defined to be 100% by weight as a whole,

a) 70 to 90% by weight of at least one compound selected from the groupconsisting of ω3 polyunsaturated fatty acids and their pharmaceuticallyacceptable salts and esters,

b) 0.5 to 6% by weight of water, and

c) 1 to 29% by weight of an emulsifying agent including either

-   -   i) a polyoxyethylene sorbitan fatty acid ester or    -   ii) at least two members selected from the group consisting of a        sorbitan fatty acid ester, a glycerin fatty acid ester and a        polyoxyethylene castor oil, or

1 to 29% by weight of an emulsifying agent including

-   -   i) a polyoxyethylene sorbitan fatty acid ester and    -   ii) at least one member selected from the group consisting of a        sorbitan fatty acid ester, a glycerin fatty acid ester and a        polyoxyethylene castor oil, wherein

d) content of ethanol and/or polyhydric alcohol is up to 4% by weight ofthe whole composition.

(1-2) A self-emulsifying composition comprising, when theself-emulsifying composition is defined to be 100% by weight as a whole,

a) 70 to 90% by weight of at least one compound selected from the groupconsisting of ω3 polyunsaturated fatty acids and their pharmaceuticallyacceptable salts and esters,

b) 0.5 to 6% by weight of water, and

c) 1 to 29% by weight of an emulsifying agent including either

-   -   i) a polyoxyethylene sorbitan fatty acid ester or    -   ii) at least two members selected from the group consisting of a        sorbitan fatty acid ester, a glycerin fatty acid ester and a        polyoxyethylene castor oil, or

1 to 29% by weight of an emulsifying agent including

-   -   i) a polyoxyethylene sorbitan fatty acid ester and    -   ii) at least one member selected from the group consisting of a        sorbitan fatty acid ester, a glycerin fatty acid ester and a        polyoxyethylene castor oil, wherein

d) content of ethanol is up to 4% by weight of the whole composition,and

e) content of polyhydric alcohol is up to 4% by weight of the wholecomposition.

(1-3) A self-emulsifying composition according to (1-1) or (1-2),wherein the polyoxyethylene sorbitan fatty acid ester is at least onemember selected from the group consisting of polyoxyethylene (20)sorbitan monolaurate, polyoxyethylene (20) sorbitan monopalmitate,polyoxyethylene (20) sorbitan monostearate, polyoxyethylene (20)sorbitan tristearate, polyoxyethylene (20) sorbitan monoisostearate,polyoxyethylene (20) sorbitan monooleate, and polyoxyethylene (20)sorbitan trioleate.

(1-4) A self-emulsifying composition according to any one of (1-1) to(1-3), wherein the sorbitan fatty acid ester is at least one memberselected from the group consisting of sorbitan monolaurate, sorbitanmonooleate, sorbitan monopalmitate, sorbitan trioleate and sorbitansesquioleate.

(1-5) A self-emulsifying composition according to any one of (1-1) to(1-4), wherein the glycerin fatty acid ester is at least one memberselected from the group consisting of glyceryl monooleate, glycerylmonostearate, decaglyceryl monooleate, decaglyceryl monolaurate,decaglyceryl trioleate, decaglyceryl pentaoleate and tetraglycerylmonooleate.

(1-6) A self-emulsifying composition according to any one of (1-1) to(1-5), wherein the polyhydric alcohol is propylene glycol or glycerin.

(1-7) A self-emulsifying composition according to any one of (1-1) to(1-5), wherein the composition contains 0 to 4% by weight of thepolyhydric alcohol.

(1-8) A self-emulsifying composition according to any one of (1-1) to(1-5), wherein the composition does not contain more than 4% by weightof the polyhydric alcohol.

(1-9) A self-emulsifying composition according to any one of (1-1) to(1-8), wherein the content of the polyhydric alcohol in the compositionis up to 1% by weight.

(1-10) A self-emulsifying composition according to any one of (1-1) to(1-8), wherein the composition contains 0 to 1% by weight of thepolyhydric alcohol.

(1-11) A self-emulsifying composition according to any one of (1-1) to(1-8), wherein the composition does not contain more than 1% by weightof the polyhydric alcohol.

(1-12) A self-emulsifying composition according to any one of (1-1) to(1-11), wherein the composition contains substantially no polyhydricalcohol.

(1-13) A self-emulsifying composition according to any one of (1-1) to(1-12), wherein the content of the ethanol in the composition is up to4% by weight.

(1-14) A self-emulsifying composition according to any one of (1-1) to(1-12), wherein the composition contains 0 to 4% by weight of theethanol.

(1-15) A self-emulsifying composition according to any one of (1-1) to(1-12), wherein the composition does not contain more than 4% by weightof the ethanol.

(1-16) A self-emulsifying composition according to any one of (1-1) to(1-15), wherein the composition contains substantially no ethanol.

(1-17) A self-emulsifying composition according to any one of (1-1) to(1-16), wherein the ω3 PUFAs and their pharmaceutically acceptable saltsand esters include at least one member selected from the groupconsisting of EPA, DHA, and their pharmaceutically acceptable salts andesters.

(1-18) A self-emulsifying composition according to any one of (1-1) to(1-17), wherein the esters of the ω3 PUFAs are ethyl esters ortriglyceride esters.

(1-19) A self-emulsifying composition according to any one of (1-1) to(1-18), wherein EPA-E or ethyl DHA ester (hereinafter abbreviated asDHA-E) is selected from among the ω3 PUFAs and their pharmaceuticallyacceptable salts and esters.

(1-20) A self-emulsifying composition according to any one of (1-1) to(1-19), which contains at least one member selected from the groupconsisting of EPA, DHA, and their pharmaceutically acceptable salts andesters as its effective component.

(1-21) A self-emulsifying composition according to any one of (1-1) to(1-20), which contains EPA-E and/or DHA-E as its effective component.

(1-22) A self-emulsifying composition according to any one of (1-1) to(1-21), which contains EPA-E as its effective component.

(1-23) A self-emulsifying composition according to any one of (1-1) to(1-22), wherein the composition contains less than 3 parts by weight oflecithin in relation to 100 parts by weight of the at least one compoundselected from the group consisting of ω3 PUFAs and theirpharmaceutically acceptable salts and esters.

(1-24) A self-emulsifying composition according to any one of (1-1) to(1-23), wherein the composition contains no lecithin.

(1-25) A self-emulsifying composition according to (1-23), wherein thelecithin is at least one member selected from the group consisting ofsoybean lecithin, zymolytic soybean lecithin, hydrogenated soybeanlecithin, and egg yolk lecithin.

(1-26) A self-emulsifying composition according to any one of (1-1) to(1-25), which has a transparent appearance when allowed to stand.

(1-27) A self-emulsifying composition according to any one of (1-1) to(1-26), which has a non-separated or non-cloudy appearance when allowedto stand.

(1-28) A self-emulsifying composition according to any one of (1-1) to(1-27), which has a transparent appearance when stored in theenvironment of 5° C. or 40° C. for 12 hours.

(1-29) A self-emulsifying composition according to any one of (1-1) to(1-28), which has a non-separated or non-cloudy appearance when storedin the environment of 5° C. or 40° C. for 12 hours.

(1-30) A self-emulsifying composition according to any one of (1-1) to(1-29), which is excellent in at least one out of self-emulsifyingproperty, composition dispersibility, and emulsion stability.

(1-31) A self-emulsifying composition according to any one of (1-1) to(1-30), which spontaneously emulsifies when 10 μL of the composition isadded dropwise to 5 mL of purified water or first fluid for dissolutiontest of Japanese Pharmacopeia at 37° C.

(1-32) A self-emulsifying composition according to any one of (1-1) to(1-31), which is dispersed by agitation when 10 μL of the composition isadded dropwise to 5 mL of purified water or first fluid for dissolutiontest of Japanese Pharmacopeia at 37° C.

(1-33) A self-emulsifying composition according to any one of (1-1) to(1-32), wherein separation of the oil component does not occur when 10μL of the composition is added dropwise to 5 mL of purified water orfirst fluid for dissolution test of Japanese Pharmacopeia at 37° C.

(1-34) A self-emulsifying composition according to any one of (1-1) to(1-33), wherein, when the self-emulsifying composition according to anyone of (1-1) to (1-33) is orally administered to a male beagle which hasbeen fasted for at least 18 hours in an amount corresponding to 600 mgof the at least one compound selected from the group consisting of ω3PUFAs and their pharmaceutically acceptable salts and esters, themaximum blood ω3 PUFA concentration is at least 50 μg/mL and/or the areaunder the blood ω3 PUFA concentration vs time curve from zero to twohours after the administration is at least 30 μg/mL·hr, or the maximumblood ω3 PUFA concentration is at least 50 μg/mL and/or the area underthe blood ω3 PUFA concentration vs time curve from zero to two hoursafter the administration is at least 50 μg/mL·hr, or the maximum bloodω3 PUFA concentration is at least 60 μg/mL and/or the area under theblood ω3 PUFA concentration vs time curve from zero to two hours afterthe administration is at least 60 μg/mL·hr, or the maximum blood ω3 PUFAconcentration is at least 70 μg/mL and/or the area under the blood ω3PUFA concentration vs time curve from zero to two hours after theadministration is at least 70 μg/mL·hr, as calculated with correction bysubtraction of the blood ω3 polyunsaturated fatty acid concentrationbefore the administration of the composition.

(1-35) A self-emulsifying composition according to any one of (1-1) to(1-33), wherein, when the self-emulsifying composition according to anyone of (1-1) to (1-33) is orally administered to a male crab-eatingmacaque which has been fasted for at least 12 hours in an amountcorresponding to 45 mg/kg body weight of the at least one compoundselected from the group consisting of ω3 PUFAs and theirpharmaceutically acceptable salts and esters, the maximum blood ω3 PUFAconcentration is at least 50 μg/mL and/or the area under the blood ω3PUFA concentration vs time curve from zero to 12 hours after theadministration is at least 400 μg/mL·hr, or the maximum blood ω3 PUFAconcentration is at least 70 μg/mL and/or the area under the blood ω3PUFA concentration vs time curve from zero to 12 hours after theadministration is at least 500 μg/mL·hr, as calculated with correctionby subtraction of the blood ω3 polyunsaturated fatty acid concentrationbefore the administration of the composition.

(1-36) A self-emulsifying composition according to any one of (1-1) to(1-33), wherein, when the self-emulsifying composition according to anyone of (1-1) to (1-33) is orally administered to a human before meals inan amount corresponding to 1800 mg of the at least one compound selectedfrom the group consisting of ω3 PUFAs and their pharmaceuticallyacceptable salts and esters, the maximum blood ω3 PUFA concentration isat least 50 μg/mL and/or the blood ω3 PUFA concentration two hours afterthe administration is at least 10 μg/mL, as calculated with correctionby subtraction of the blood ω3 polyunsaturated fatty acid concentrationbefore the administration of the composition.

(1-37) A self-emulsifying composition according to any one of (1-1) to(1-33), wherein, when the self-emulsifying composition according to anyone of (1-1) to (1-33) is orally administered to a human before meals inan amount corresponding to 1800 mg of the at least one compound selectedfrom the group consisting of ω3 PUFAs and their pharmaceuticallyacceptable salts and esters, the maximum blood ω3 PUFA concentration isat least 10 μg/mL and/or the area under the blood ω3 PUFA concentrationvs time curve from zero to 72 hours after the administration is at least250 μg/mL·hr, as calculated with correction by subtraction of the bloodω3 polyunsaturated fatty acid concentration before the administration ofthe composition.

(1-38) A self-emulsifying composition comprising, when theself-emulsifying composition is defined to be 100% by weight as a whole,

a) 70 to 90% by weight of EPA-E,

b) 0.5 to 6% by weight of water, and

c) 1 to 29% by weight of an emulsifying agent including either

-   -   i) a polyoxyethylene sorbitan fatty acid ester or    -   ii) at least two members selected from the group consisting of a        sorbitan fatty acid ester, a glycerin fatty acid ester and a        polyoxyethylene castor oil, or

1 to 29% by weight of an emulsifying agent including

-   -   i) a polyoxyethylene sorbitan fatty acid ester and    -   ii) at least one member selected from the group consisting of a        sorbitan fatty acid ester, a glycerin fatty acid ester and a        polyoxyethylene castor oil, wherein

d) content of ethanol and/or polyhydric alcohol is up to 4% by weight ofthe whole composition, and

e) content of lecithin is less than 3 parts by weight in relation to 100parts by weight of a).

(1-39) A self-emulsifying composition comprising, when theself-emulsifying composition is defined to be 100% by weight as a whole,

a) 70 to 90% by weight of EPA-E,

b) 0.5 to 6% by weight of water, and

c) 1 to 29% by weight of an emulsifying agent including either

-   -   i) a polyoxyethylene sorbitan fatty acid ester or    -   ii) at least two members selected from the group consisting of a        sorbitan fatty acid ester, a glycerin fatty acid ester and a        polyoxyethylene castor oil, or

1 to 29% by weight of an emulsifying agent including

-   -   i) a polyoxyethylene sorbitan fatty acid ester and    -   ii) at least one member selected from the group consisting of a        sorbitan fatty acid ester, a glycerin fatty acid ester and a        polyoxyethylene castor oil, wherein

d) content of ethanol is up to 4% by weight of the whole composition,

e) content of polyhydric alcohol is up to 4% by weight of the wholecomposition, and

f) content of lecithin is less than 3 parts by weight in relation to 100parts by weight of a).

A second aspect of the present invention is the capsulatedself-emulsifying preparation as described below.

(2-1) A capsulated self-emulsifying preparation having theself-emulsifying composition according to any one of (1-1) to (1-39)encapsulated in a hard capsule and/or a soft capsule as a liquidcontent.

(2-2) A capsulated self-emulsifying preparation according to (2-1),which exhibits sufficient hardness immediately after its production.

(2-3) A capsulated self-emulsifying preparation according to (2-1) or(2-2), which has a hardness of 18 kgf or more immediately after itsproduction.

(2-4) A capsulated self-emulsifying preparation according to any one of(2-1) to (2-3), which does not experience loss of its hardness of 6 kgfor more when sealed in an aluminum package and stored at 40° C. for 1week, and then compared with the preparation before the storage.

(2-5) A capsulated self-emulsifying preparation according to any one of(2-1) to (2-4), which has a hardness of 20 kgf or more when sealed in analuminum package and stored at 40° C. for 1 week.

(2-6) A capsulated self-emulsifying preparation according to any one of(2-1) to (2-5), which, when sealed in an aluminum package and stored at40° C. for 1 week, retains 60% or more of its hardness before thestorage.

(2-7) A preparation according to (2-1), which serves as at least onedrug selected from the group consisting of therapeutic agent fordyslipidemia (hypercholesterolemia, LDL hypercholesterolemia, non-HDLhypercholesterolemia, VLDL hypercholesterolemia, HDLhypocholesterolemia, hypertriglyceridemia, apo B hyperlipoproteinemia,apo A-I hypolipoproteinemia, and so forth), therapeutic agent forpostprandial hypertriglyceridemia, anti-arteriosclerosis agent, plateletaggregation suppressant, therapeutic agent for peripheral circulatoryinsufficiency, prophylactic agent for cardiovascular events, therapeuticagent for inflammatory disease (non-alcoholic fatty liver disease(hereafter abbreviated as NAFLD), non-alcoholic steatohepatitis(hereafter abbreviated as NASH), and so forth), progression suppressantand therapeutic agent for cognitive impairment (dementia of theAlzheimer's type, cerebrovascular dementia, mixed type of dementia, andso forth), anticancer agent, and therapeutic agent for central disease(depression, depressive condition, obsessive-compulsive disorder, socialanxiety disorder, panic disorder, and so forth).

A third aspect of the present invention is the method for producing aself-emulsifying composition as described below.

(3-1) A method for producing a self-emulsifying composition, comprisingthe step of:

mixing the following components a) to c) in any order while defining theself-emulsifying composition to be 100% by weight as a whole,

a) 70 to 90% by weight of at least one compound selected from the groupconsisting of ω3 polyunsaturated fatty acids and their pharmaceuticallyacceptable salts and esters,

b) 0.5 to 6% by weight of water, and

c) 1 to 29% by weight of an emulsifying agent including either

-   -   i) a polyoxyethylene sorbitan fatty acid ester or    -   ii) at least two members selected from the group consisting of a        sorbitan fatty acid ester, a glycerin fatty acid ester and a        polyoxyethylene castor oil, or

1 to 29% by weight of an emulsifying agent including

-   -   i) a polyoxyethylene sorbitan fatty acid ester and    -   ii) at least one member selected from the group consisting of a        sorbitan fatty acid ester, a glycerin fatty acid ester and a        polyoxyethylene castor oil, so that, in the resultant        composition,

d) content of ethanol and/or polyhydric alcohol may be up to 4% byweight of the whole composition.

(3-2) A method for producing a self-emulsifying composition, comprisingthe step of:

mixing the following components a) to c) in any order while defining theself-emulsifying composition to be 100% by weight as a whole,

a) 70 to 90% by weight of at least one compound selected from the groupconsisting of ω3 polyunsaturated fatty acids and their pharmaceuticallyacceptable salts and esters,

b) 0.5 to 6% by weight of water, and

c) 1 to 29% by weight of an emulsifying agent including either

-   -   i) a polyoxyethylene sorbitan fatty acid ester or    -   ii) at least two members selected from the group consisting of a        sorbitan fatty acid ester, a glycerin fatty acid ester and a        polyoxyethylene castor oil, or

1 to 29% by weight of an emulsifying agent including

-   -   i) a polyoxyethylene sorbitan fatty acid ester and    -   ii) at least one member selected from the group consisting of a        sorbitan fatty acid ester, a glycerin fatty acid ester and a        polyoxyethylene castor oil, so that, in the resultant        composition,

d) content of ethanol may be up to 4% by weight of the wholecomposition, and

e) content of polyhydric alcohol may be up to 4% by weight of the wholecomposition.

(3-3) A method for producing a self-emulsifying composition according to(3-1) or (3-2), further comprising the step of heating the a), b),and/or c) to a temperature of 70° C. or higher before the mixing step.

A fourth aspect of the present invention is the pharmaceuticalpreparation as described below for administering a self-emulsifyingcomposition by a particular method.

(4-1) A preparation for orally administering at least oneself-emulsifying composition or capsulated self-emulsifying preparation,drug or veterinary drug selected from among those according to (1-1) to(1-39), (2-1) to (2-7) and (3-1) to (3-3) under fasting or at bedtime.

(4-2) A preparation for orally administering the self-emulsifyingcomposition or capsulated self-emulsifying preparation, drug orveterinary drug as produced by the production method according to anyone of (3-1) to (3-3) under fasting or at bedtime.

(4-3) A preparation according to (4-1) or (4-2), which serves as atleast one member selected from the group consisting of therapeutic agentfor dyslipidemia (hypercholesterolemia, LDL hypercholesterolemia,non-HDL hypercholesterolemia, VLDL hypercholesterolemia, HDLhypocholesterolemia, hypertriglyceridemia, apo B hyperlipoproteinemia,apo A-I hypolipoproteinemia, and so forth), therapeutic agent forpostprandial hypertriglyceridemia, anti-arteriosclerosis agent, plateletaggregation suppressant, therapeutic agent for peripheral circulatoryinsufficiency, prophylactic agent for cardiovascular events, therapeuticagent for inflammatory disease (NAFLD, NASH, and so forth), progressionsuppressant and therapeutic agent for cognitive impairment (dementia ofthe Alzheimer's type, cerebrovascular dementia, mixed type of dementia,and so forth), anticancer agent, as well as prophylactic agent,therapeutic agent and progression preventing agent for central disease(depression, depressive condition, obsessive-compulsive disorder, socialanxiety disorder, panic disorder, and so forth).

(4-4) A preparation according to any one of (4-1) to (4-3), which isadministered once a day.

(4-5) A method for administering and/or using the preparation accordingto any one of (4-1) to (4-4).

(4-6) A method for increasing the concentration of ω3 PUFA in plasma bythe oral administration as stated in any one of (4-1) to (4-4).

A fifth aspect of the present invention is a method of prophylaxis,progression prevention, and therapy for at least one disease selectedfrom the group below.

(5-1) A method of prophylaxis, progression prevention, and therapy forat least one disease selected from the group consisting of dyslipidemia(hypercholesterolemia, LDL hypercholesterolemia, non-HDLhypercholesterolemia, VLDL hypercholesterolemia, HDLhypocholesterolemia, hypertriglyceridemia, apo B hyperlipoproteinemia,apo A-I hypolipoproteinemia, and so forth), postprandialhypertriglyceridemia, arteriosclerosis, increase of plateletaggregation, peripheral circulatory insufficiency, onset of acardiovascular event, inflammatory disease (NAFLD, NASH, and so forth),cognitive impairment (dementia of the Alzheimer's type, cerebrovasculardementia, mixed type of dementia, and so forth), cancer, and centraldisease (depression, depressive condition, obsessive-compulsivedisorder, social anxiety disorder, panic disorder, and so forth),comprising the step of orally administering at least oneself-emulsifying composition or capsulated self-emulsifying preparation,drug or veterinary drug selected from among those according to (1-1) to(1-39), (2-1) to (2-7) and (3-1) to (3-3) to a patient.

(5-2) A method according to (5-1), wherein the self-emulsifyingcomposition or capsulated self-emulsifying preparation, drug orveterinary drug is orally administered under fasting or at bedtime.

(5-3) A method according to (5-1) or (5-2), wherein the self-emulsifyingcomposition or capsulated self-emulsifying preparation, drug orveterinary drug is administered once a day.

A sixth aspect of the present invention is the self-emulsifyingcomposition as described below.

(6-1) A self-emulsifying composition, wherein, when the self-emulsifyingcomposition is orally administered to a male beagle which has beenfasted for at least 18 hours in an amount corresponding to 600 mg of atleast one compound selected from the group consisting of ω3 PUFAs andtheir pharmaceutically acceptable salts and esters, the maximum blood ω3PUFA concentration is at least 50 μg/mL and/or the area under the bloodω3 PUFA concentration vs time curve from zero to two hours after theadministration is at least 30 μg/mL hr, or the maximum blood ω3 PUFAconcentration is at least 50 μg/mL and/or the area under the blood ω3PUFA concentration vs time curve from zero to two hours after theadministration is at least 50 μg/mL·hr, or the maximum blood ω3 PUFAconcentration is at least 60 μg/mL and/or the area under the blood ω3PUFA concentration vs time curve from zero to two hours after theadministration is at least 60 μg/mL·hr, or the maximum blood ω3 PUFAconcentration is at least 70 μg/mL and/or the area under the blood ω3PUFA concentration vs time curve from zero to two hours after theadministration is at least 70 μg/mL·hr, as calculated with correction bysubtraction of the blood ω3 polyunsaturated fatty acid concentrationbefore the administration of the composition.

(6-2) A self-emulsifying composition, wherein, when the self-emulsifyingcomposition is orally administered to a male crab-eating macaque whichhas been fasted for at least 12 hours in an amount corresponding to 45mg/kg body weight of at least one compound selected from the groupconsisting of ω3 PUFAs and their pharmaceutically acceptable salts andesters, the maximum blood ω3 PUFA concentration is at least 50 μg/mLand/or the area under the blood ω3 PUFA concentration vs time curve fromzero to 12 hours after the administration is at least 400 μg/mL·hr, orthe maximum blood ω3 PUFA concentration is at least 70 μg/mL and/or thearea under the blood ω3 PUFA concentration vs time curve from zero to 12hours after the administration is at least 500 μg/mL·hr, as calculatedwith correction by subtraction of the blood ω3 polyunsaturated fattyacid concentration before the administration of the composition.

(6-3) A self-emulsifying composition, wherein, when the self-emulsifyingcomposition is orally administered to a human before meals in an amountcorresponding to 1800 mg of at least one compound selected from thegroup consisting of ω3 PUFAs and their pharmaceutically acceptable saltsand esters, the maximum blood ω3 PUFA concentration is at least 50 μg/mLand/or the blood ω3 PUFA concentration two hours after theadministration is at least 10 μg/mL, as calculated with correction bysubtraction of the blood ω3 polyunsaturated fatty acid concentrationbefore the administration of the composition.

(6-4) A self-emulsifying composition, wherein, when the self-emulsifyingcomposition is orally administered to a human before meals in an amountcorresponding to 1800 mg of at least one compound selected from thegroup consisting of ω3 PUFAs and their pharmaceutically acceptable saltsand esters, the maximum blood ω3 PUFA concentration is at least 10 μg/mLand/or the area under the blood ω3 PUFA concentration vs time curve fromzero to 72 hours after the administration is at least 250 μg/mL·hr, ascalculated with correction by subtraction of the blood ω3polyunsaturated fatty acid concentration before the administration ofthe composition.

Advantageous Effects of Invention

The self-emulsifying composition of the present invention contains asmall amount of water instead of the ethanol and the polyhydric alcoholin its composition. Compatibility of the composition improves by suchcomposition, and amount of the emulsifier used can also be reduced, andaccordingly, safety for animals (including human) is thereby improved.In addition, the ω3 PUFA will be included at a higher content, and thisenables reduction in the amount of emulsifier used, and compliance isthereby improved.

Inclusion of the water in the composition also enables a compositionwithout or with minimized use of the ethanol or the polyhydric alcohols,and hence, prevention of the softening of the capsule film, anddeformation of the capsule.

The self-emulsifying composition of the present invention is excellentin at least one out of compatibility (appearance), self-emulsifyingproperty, composition dispersibility, emulsion stability, andabsorbability, and it will be rapidly absorbed even if administeredbefore meals or after the intake of low fat diet to suppress theincrease in serum TG after meals or, if administered at bedtime, it willprevent the essential fatty acid deficiency in a subject taking a lipaseinhibitor.

In addition, the inventive self-emulsifying composition is free fromseparation and cloudiness, that is to say, maintains good appearancewhen stored at room temperature, a lower temperature (e.g., 5° C.) or ahigher temperature (e.g., 40° C.). Preferably, the composition is freefrom separation and cloudiness and thus maintains good appearance underany two out of the above temperature conditions, more preferably underall three conditions.

The self-emulsifying composition of the present invention has at leastone, preferably at least two, and more preferably all of theadvantageous characters as described above.

DESCRIPTION OF EMBODIMENTS

Next, the present invention is described in detail.

The present invention relates to a self-emulsifying compositioncomprising 70 to 90% by weight in total of at least one compoundselected from the group consisting of ω3 polyunsaturated fatty acids andtheir pharmaceutically acceptable salts and esters and 1 to 29% byweight of a particular emulsifying agent and having low or no content ofethanol or polyhydric alcohol, a capsulated self-emulsifying preparationhaving such self-emulsifying composition encapsulated as a content, anda pharmaceutical preparation, a production method and a method of usethereof.

In the present invention, “ω3 PUFA” is a fatty acid having a pluralityof carbon—carbon double bonds in the molecule, and the first double bondis at 3rd position from the end on the side of the methyl group. Typicalexamples include α-linolenic acid, EPA, DHA, eicosatrienoic acid,stearidonic acid, eicosatetraenoic acid, clupanodonic acid,tetracosapentaenoic acid, and nisinic acid. Unless otherwise specified,the terms “ω3 PUFA,” “EPA,” “DHA” and “fatty acid” as used in thepresent invention mean a ω3 PUFA, EPA, DHA and a fatty acid inclusive ofpharmaceutically acceptable salts and esters thereof, respectively.

The ω3 PUFA used in the present invention may be a synthetic,semi-synthetic, natural ω3 PUFA, or a natural oil containing such ω3PUFA. Examples of the natural ω3 PUFA include an extract from a naturaloil containing an ω3 PUFA, a crudely purified natural oil containing anω3 PUFA, and a highly purified natural oil containing an ω3 PUFAproduced by a method known in the art. Exemplary semi-synthetic ω3 PUFAsinclude ω3 PUFAs produced by a microorganism or the like and the ω3PUFAs or the natural ω3 PUFAs which have been subjected to a chemicaltreatment such as esterification or ester exchange. In the presentinvention, the ω3 PUFAs may be used alone or in combination of two ormore.

In the present invention, EPA and DHA are the preferable examples of theω3 PUFAs, and EPA is more preferable. Examples of the pharmaceuticallyacceptable salts of the ω3 PUFA include inorganic salts such as sodiumsalts and potassium salts, organic salts such as benzylamine salts anddiethylamine salts, salts with basic amino acids such as arginine saltsand lysine salts, and exemplary esters include alkyl esters such asethyl ester, and esters such as monoglyceride, diglyceride andtriglyceride. Preferable examples include ethyl ester and TG ester, andthe more preferred is ethyl ester. More specifically, preferableexamples include EPA-E, TG ester of EPA, DHA-E, and TG ester of DHA, andamong these, the more preferred are EPA-E and DHA-E, and the mostpreferred is EPA-E.

The ω3 PUFA used as a starting material of the self-emulsifyingcomposition of the present invention is not particularly limited inpurity. The purity is typically such that the content of the ω3 PUFA inrelation to the total fatty acid contained in the composition of thepresent invention could be preferably at least 50% by weight, morepreferably at least 70% by weight, still more preferably at least 80% byweight, still more preferably at least 90% by weight, still morepreferably at least 96.5% by weight, and most preferably at least 98% byweight. The ω3 PUFA containing EPA at a high purity, for example, theone with an EPA content of at least 50% by weight is preferable, and thecontent is more preferably at least 60% by weight, still more preferablyat least 70% by weight, still more preferably at least 80% by weight,still more preferably at least 90% by weight, even more preferably atleast 96.5% by weight, and most preferably at least 98% by weight. Inother words, the composition of the present invention preferably has ahigh purity of ω3 PUFAs in the total fatty acid, more preferably, a highpurity of EPA+DHA as ω3 PUFAs, and most preferably has EPA at such apurity that EPA is essentially associated with no DHA or merely with,for instance, less than 1.0%, preferably less than 0.5%, and morepreferably less than 0.2% of DHA.

For example, when EPA-E and DHA-E are used, compositional ratio ofEPA-E/DHA-E and content of (EPA-E+DHA-E) in relation to the total fattyacid are not particularly limited as long as the purity of EPA-E in thecomposition of the present invention is in the range as described above.However, the compositional ratio of the EPA-E/DHA-E is preferably atleast 0.8, more preferably at least 1.0, and most preferably at least1.2.

The composition of the present invention may also contain apolyunsaturated fatty acid other than the ω3 PUFA, such as linoleicacid, γ linolenic acid or dihomo-γ-linolenic acid, or a pharmaceuticallyacceptable salt or ester thereof. It, however, is desirable that thecontent of arachidonic acid or a pharmaceutically acceptable salt orester thereof is low, preferably less than 2% by weight, and morepreferably less than 1% by weight. Particularly preferred is thecomposition which is essentially free from arachidonic acid andpharmaceutically acceptable salts and esters thereof.

In the self-emulsifying composition of the present invention, content ofthe ω3 PUFA is 70 to 90% by weight, preferably 70 to 86% by weight, morepreferably 72 to 85% by weight, and still more preferably 74 to 84% byweight. The ω3 PUFA may be a single ω3 PUFA or a mixture of two or moreones. If a mixture is used, the content of mixed fatty acids in theself-emulsifying composition is 70 to 90% by weight in total.

The ω3 PUFA used may be a soft capsule containing the EPA-E at a highpurity (at least 96.5% by weight) (product name, Epadel; manufactured byMochida Pharmaceutical Co., Ltd.) commercially available in Japan as atherapeutic agent for ASO and hyperlipidemia or a high purity EPA-Econtaining capsule (product name, VASCEPA; Amarin) commerciallyavailable in the U.S. as a therapeutic agent for hypertriglyceridemia.The ω3 PUFA used may also be a mixture of EPA-E and DHA-E, for example,Lovaza (Registered Trademark) (a soft capsule containing about 46.5% byweight of EPA-E and about 37.5% by weight of DHA-E from GlaxoSmithKline)commercially available in the U.S. as a therapeutic agent forhypertriglyceridemia or LOTRIGA (Registered Trademark) (a soft capsulecontaining about 46.5% by weight of EPA-E and about 37.5% by weight ofDHA-E from Takeda Pharmaceutical Co., Ltd.) commercially available inJapan. It is also possible to use a mixture of EPA and DHA such asEpanova (Registered Trademark) (a soft capsule containing about 50 to60% by weight of EPA free acid and about 15 to 25% by weight of DHA freeacid from AstraZeneca) commercially available in the U.S. as atherapeutic agent for hypertriglyceridemia.

Purified fish oils may also be used for the ω3 PUFA, and uses ofmonoglyceride(MG), diglyceride(DG), and TG derivatives and combinationsthereof as the ω3 PUFA are also preferable embodiments. Various productscontaining the ω3 PUFA are commercially available, for example,Incromega F2250, F2628, E2251, F2573, TG2162, TG2779, TG2928, TG3525,and E5015 (Croda International PLC, Yorkshire, England), and EPAX6000FA,EPAX5000TG, EPAX4510TG, EPAX2050TQ EPAX7010EE, K85TG, K85EE, and K80EE(Pronova Biopharma, Lysaker, Norway). These products may be purchasedand used for the composition of the present invention.

In the present invention, the “polyoxyethylene sorbitan fatty acidester” is polyoxyethylene ether of a fatty acid ester wherein a part ofthe hydroxy groups of anhydrous sorbitol have been esterified with afatty acid. Various compounds with different esterifying fatty acids arecommercially available, and examples include polyoxyethylene (20)sorbitan monolaurate (NIKKOL TL-10, polysorbate 20, Tween 20),polyoxyethylene (20) sorbitan monopalmitate (NIKKOL TP-10V, Polysorbate40, Tween 40), polyoxyethylene (20) sorbitan monostearate (NIKKOLTS-10MV, polysorbate 60, Tween 60), polyoxyethylene (20) sorbitantristearate (NIKKOL TS-30V, polysorbate 65), polyoxyethylene (20)sorbitan monoisostearate (NIKKOL TI-10V), polyoxyethylene (20) sorbitanmonooleate (NIKKOL TO-10MV, polysorbate 80, Tween 80), andpolyoxyethylene (20) sorbitan trioleate (NIKKOL TO-30V, polysorbate 85),and the preferred are polyoxyethylene (20) sorbitan monostearate,polyoxyethylene (20) sorbitan monooleate, and polyoxyethylene (20)sorbitan trioleate, and the more preferred is polyoxyethylene (20)sorbitan monooleate.

These may be used alone or in combination of two or more. The term“polyoxyethylene sorbitan fatty acid ester” as used in the presentinvention means all of such compounds.

Content of the polyoxyethylene sorbitan fatty acid ester in theself-emulsifying composition of the present invention is notparticularly limited as long as the merits of the present invention arenot adversely affected. The content is generally 1 to 29% by weight,preferably 5 to 20% by weight, and more preferably 7 to 15% by weightwhen the self-emulsifying composition is defined to be 100% by weight asa whole.

In the present invention, the “sorbitan fatty acid ester” is a compoundobtained by esterifying hydroxy groups of anhydrous sorbitol with afatty acid. Various compounds with different esterifying fatty acids arecommercially available, and examples include sorbitan monolaurate (Span20; NIKKOL SL-10; Nonion LP-20R), sorbitan monostearate (NIKKOLSS-10MV), sorbitan monooleate (Span 80; NIKKOL SO-10V), sorbitanmonopalmitate (Span 40; NIKKOL SP-10V), sorbitan trioleate (NIKKOLSO-30) and sorbitan sesquioleate (Span 83; NIKKOL SO-15MV; NonionOP-83R), with sorbitan monolaurate, sorbitan monooleate and sorbitansesquioleate, among orhers sorbitan monolaurate, being preferred. Thesemay be used alone or in combination of two or more. The term “sorbitanfatty acid ester” as used in the present invention means all of suchcompounds.

Content of the sorbitan fatty acid ester in the self-emulsifyingcomposition of the present invention is not particularly limited as longas the merits of the present invention are not adversely affected. Thecontent is generally 1 to 20% by weight, preferably 2 to 15% by weight,and more preferably 3 to 10% by weight when the self-emulsifyingcomposition is defined to be 100% by weight as a whole, or 2 to 8% byweight, preferably 2 to 7% by weight, and more preferably 3 to 5% byweight when the self-emulsifying composition is defined to be 100% byweight as a whole.

In the present invention, the “glycerin fatty acid ester” is an ester ofa fatty acid and glycerin or polyglycerin and derivatives thereof(including glycerin fatty acid ester, acetic and fatty acid esters ofglycerol, lactic and fatty acid esters of glycerol, citric and fattyacid esters of glycerol, succinic and fatty acid esters of glycerol,diacetyl tartaric and fatty acid esters of glycerol, glycerin aceticacid ester, polyglycrin fatty acid ester, and polygrycelin condensedricinoleic acid ester).

Various compounds are commercially available, and examples includeglyceryl monooleate (PECEOL), glyceryl monostearate (NIKKOL MGS-F50SEV,MGS-AMV, MGS-BMV), decaglyceryl monooleate (NIKKOL Decaglyn 1-OV; POEMJ-0381V), decaglyceryl monolaurate (NIKKOL Decaglyn 1-L), dacaglyceryltrioleate (NIKKOL Decaglyn 3-OV), decaglyceryl pentaoleate (NIKKOLDecaglyn 5-OV) and tetraglyceryl monooleate (NIKKOL Tetraglyn 1-OV),with glyceryl monooleate, decaglyceryl monooleate and glycerylmonostearate, among others decaglyceryl monooleate, being preferred.These may be used alone or in combination of two or more. The term“glycerin fatty acid ester” as used in the present invention means allof such compounds.

Content of the glycerin fatty acid ester in the self-emulsifyingcomposition of the present invention is not particularly limited as longas the merits of the present invention are not adversely affected. Thecontent is generally 1 to 25% by weight, preferably 3 to 20% by weight,more preferably 5 to 15% by weight, and even more preferably 6 to 10% byweight when the self-emulsifying composition is defined to be 100% byweight as a whole, or 1 to 20% by weight, preferably 1 to 15% by weight,more preferably 1 to 10% by weight, and even more preferably 1 to 8% byweight when the self-emulsifying composition is defined to be 100% byweight as a whole.

In the present invention, the “polyoxyethylene castor oil” is a compoundprepared by addition polymerization of ethylene oxide to castor oil.Various compounds with different average degrees of polymerization ofethylene oxide are commercially available, and examples include NIKKOLCO-3 (Nikko Chemicals Co., Ltd.) with an average ethylene oxide molenumber of 3, NIKKOL CO-10 (Nikko Chemicals Co., Ltd.) with an averageethylene oxide mole number of 10, EMALEX C-20 (Nippon Emulsion Co.,Ltd.) with an average ethylene oxide mole number of 20, EMALEX C-30(Nippon Emulsion Co., Ltd.) with an average ethylene oxide mole numberof 30, Kolliphor EL (BASF) (polyoxyl 35 castor oil) with an averageethylene oxide mole number of 35, EMALEX C-40 (Nippon Emulsion Co.,Ltd.) with an average ethylene oxide mole number of 40, and EMALEX C-50(Nippon Emulsion Co., Ltd.) with an average ethylene oxide mole numberof 50, and the preferred is Kolliphor EL. These may be used alone or incombination of two or more. The term “polyoxyethylene castor oil” asused in the present invention means all of such compounds unlessotherwise noted.

Content of the polyoxyethylene castor oil in the self-emulsifyingcomposition of the present invention is not particularly limited as longas the merits of the present invention are not adversely affected. Thecontent is generally 1 to 20% by weight, preferably 2 to 15% by weight,more preferably 3 to 10% by weight, and even more preferably 4 to 6% byweight when the self-emulsifying composition is defined to be 100% byweight as a whole.

Preferred embodiments of the self-emulsifying composition of theinvention are as described in the following i) and/or ii).

i) A preferred embodiment of the inventive self-emulsifying compositioncontains at least a polyoxyethylene sorbitan fatty acid ester as anemulsifier. More preferably, the inventive composition contains apolyoxyethylene sorbitan fatty acid ester as a chief emulsifier. Inanother preferred embodiment, the emulsifying agent to be used for thecomposition is essentially composed of a polyoxyethylene sorbitan fattyacid ester and at least one selected from among a sorbitan fatty acidester, a glycerin fatty acid ester and a polyoxyethylene castor oil.

The amount of a polyoxyethylene sorbitan fatty acid ester contained as achief emulsifier will be at least 40 parts by weight, preferably atleast 50 parts by weight, and more preferably at least 60 parts byweight when the total amount of emulsifiers contained in the compositionis defined as 100 parts by weight. The amount of at least one emulsifierselected from among a sorbitan fatty acid ester, a glycerin fatty acidester and a polyoxyethylene castor oil and used in combination with thepolyoxyethylene sorbitan fatty acid ester will be up to 60 parts byweight, preferably up to 50 parts by weight, and more preferably up to40 parts by weight when the total amount of the emulsifying agent to beused for the composition is defined as 100 parts by weight.

ii) Still another preferred embodiment of the inventive self-emulsifyingcomposition contains at least two selected from among a sorbitan fattyacid ester, a glycerin fatty acid ester and a polyoxyethylene castoroil. This embodiment may not contain a polyoxyethylene sorbitan fattyacid ester.

While the combination of two emulsifiers is not particularly limited,preferred are combinations of a sorbitan fatty acid ester and apolyoxyethylene castor oil, of a glycerin fatty acid ester and apolyoxyethylene castor oil, and of a sorbitan fatty acid ester and aglycerin fatty acid ester, with a combination of a sorbitan fatty acidester and a polyoxyethylene castor oil and a combination of a glycerinfatty acid ester and a polyoxyethylene castor oil being more preferred.

In this embodiment, the amount of an emulsifier contained in thecomposition in a larger amount than any other emulsifier is preferablyup to 75 parts by weight, more preferably up to 67 parts by weight, andeven more preferably up to 60 parts by weight when the total amount ofemulsifiers contained in the composition is defined as 100 parts byweight. In some cases, the amount of such emulsifier is preferably 30 to80 parts by weight, more preferably 35 to 70 parts by weight, even morepreferably 38 to 67 parts by weight, and most preferably 40 to 55 partsby weight.

In the self-emulsifying composition of the present invention, aplurality of emulsifiers including a polyoxyethylene castor oil may beused as an emulsifying agent. The amount of polyoxyethylene castor oilcontained in the composition is preferably up to 70 parts by weight,more preferably up to 60 parts by weight, and even more preferably up to50 parts by weight when the total amount of emulsifiers contained in thecomposition is defined as 100 parts by weight. In some cases, the amountof polyoxyethylene castor oil is preferably 10 to 70 parts by weight,more preferably 15 to 60 parts by weight, even more preferably 17 to 40parts by weight, and most preferably 18 to 30 parts by weight.

The self-emulsifying composition of the present invention may alsocontain an emulsifier other than the polyoxyethylene sorbitan fatty acidester, sorbitan fatty acid ester, glycerin fatty acid ester andpolyoxyethylene castor oil, while the amount of such an emulsifier is upto 20 parts by weight, preferably up to 10 parts by weight, morepreferably up to 5 parts by weight, and most preferably none when thetotal amount of emulsifiers used for the composition is defined as 100parts by weight. The additional emulsifier is not particularly limitedas long as it satisfies at least one of the demands as described above,and exemplary additional emulsifiers include polyoxyethylenehydrogenated castor oil, propylene glycol fatty acid ester, saturatedpolyglycolated glyceride, polyoxyethylene polypropylene glycol, andsucrose fatty acid ester.

The total content of emulsifiers in the self-emulsifying composition ofthe present invention is not particularly limited as long as the meritsof the present invention are not adversely affected. The totalemulsifier content is generally 1 to 29% by weight, preferably 5 to 29%by weight, more preferably 6 to 29% by weight, still more preferably 7to 29% by weight, and even more preferably 8 to 29% by weight,especially 9 to 29% by weight, when the self-emulsifying composition isdefined to be 100% by weight as a whole. In some cases, the totalemulsifier content is preferably 5 to 24% by weight, and more preferably10 to 20% by weight. In alternative cases, the total emulsifier contentis preferably 6 to 28% by weight, more preferably 8 to 26% by weight,and even more preferably 9 to 25% by weight. In addition, the totalamount of emulsifiers contained in the composition is 5 to 45 parts byweight, preferably 10 to 45 parts by weight, more preferably 15 to 35parts by weight, and even more preferably 15 to 20 parts by weight inrelation to 100 parts by weight of the ω3 PUFA.

The composition and the pharmaceutical preparation of the presentinvention contain a small amount of water. Addition of water to acomposition containing a hydrophobic lipid is generally conceived as aloss of compatibility. Presence of a specified amount of water in theinventive composition results in an improved compatibility of thecomposition, makes the use of a polyhydric alcohol and ethanolunnecessary, and thus allows the product which has a transparentappearance and gets rid of the problem of separation or cloudiness of acomposition, even though not containing a polyhydric alcohol, ethanol orlecithin.

A small amount of water may be added during the preparation of theself-emulsifying composition, or the water in the gelatin capsule filmmay transfer to the self-emulsifying composition after the encapsulationof the self-emulsifying composition in the capsule.

In addition, the composition free from the polyhydric alcohol and theethanol does not cause the capsule to be softened or deformed after theencapsulation, nor has side effects of the ethanol on alcoholintolerance patients taking the composition.

The water content of the self-emulsifying composition is preferably 0.5to 6% by weight, more preferably 0.5 to 4% by weight, still morepreferably 0.5 to 3% by weight, and even more preferably 0.5 to 2.5% byweight, with a content of 0.7 to 1.5% by weight being most preferred,when the composition is defined to be 100% by weight as a whole.

The water content is preferably 1 to 30% by weight, more preferably 2 to25% by weight, still more preferably 3 to 20% by weight, and even morepreferably 4 to 15% by weight, with a content of 5 to 9% by weight beingmost preferred, when the total amount of emulsifiers contained in theself-emulsifying composition is defined as 100 parts by weight.

In the present invention, the “lecithin” is a type ofglycerophospholipid, and examples include soybean lecithin, zymolyticsoybean lecithin, hydrogenated soybean lecithin, egg yolk lecithin,hydrogenated phospholipid, phospholipid from milk, lysolecithin,phosphatidyl choline, and phosphatidyl serine. The preferred are soybeanlecithin, zymolytic soybean lecithin, hydrogenated soybean lecithin, andegg yolk lecithin, and the more preferred is soybean lecithin. These maybe used alone or in combination of two or more. The term “lecithin” asused in the present invention means all of such glycerophospholipidsunless otherwise noted. In the present invention, lecithin is notincluded in the emulsifying agent.

Various lecithins are commercially available, and exemplary suchproducts include purified soybean lecithin (Nisshin Oilio), purified eggyolk lecithin (Asahi Kasei Pharma Corporation), and egg yolk lecithinPL-100M (Kewpie Corporation), and use of such products is also possible.Exemplary soybean lecithins include BASIS LP-20B (Nisshin Oil Mills,Ltd.) and Lipoid S45 and S20 (Lipoid), and exemplary zymolytic lecithinsinclude BASIS LP-20E (Nisshin Oil Mills, Ltd.) and Phospholipon RLPC20(Lipoid). Various such commercially available products may be used inthe composition.

In a preferred embodiment of the self-emulsifying composition of thepresent invention, essentially no lecithin is contained. For instance, 3or more parts by weight of lecithin is not contained in the compositionin relation to 100 parts by weight of the ω3 PUFA. In other words, theamount of lecithin contained in the composition is less than 3 parts byweight, preferably less than 2 parts by weight, more preferably lessthan 1 part by weight, and most preferably 0 parts by weight. The amountof lecithin contained in the inventive self-emulsifying composition ispreferably 0 parts by weight or more but less than 3 parts by weight,and more preferably 0 parts by weight or more but less than 1 part byweight.

The lecithin content is preferably lower than 2.1% by weight, morepreferably lower than 1.4% by weight, and even more preferably lowerthan 0.7% by weight when the self-emulsifying composition is defined tobe 100% by weight as a whole.

In the present invention, the “polyhydric alcohol” is a polyol compoundhaving the structure of a straight chain or cyclic aliphatic hydrocarbonwherein two or more carbon atoms are each substituted with one hydroxygroup. Exemplary such polyhydric alcohols include divalent alcohols suchas ethylene glycol, propylene glycol, trimethylene glycol, 1,2-butyleneglycol, tetramethylene glycol, 1,3-butylene glycol, 2,3-butylene glycol,and pentamethylene glycol; trivalent alcohols such as glycerin,trimethylolpropane, and 1,2,6-hexane triol; and polyhydric alcoholpolymers such as diethylene glycol, dipropylene glycol triethyleneglycol, polyethylene glycol, polypropylene glycol, and polyglycerin, andthe preferred is propylene glycol or glycerin. The glycerin alsoincludes concentrated glycerin. The term “polyhydric alcohol” as used inthe present invention means all of such polyol compounds unlessotherwise noted.

Advantageously, the content of the polyhydric alcohol in theself-emulsifying composition of the present invention is such that itdoes not cause a capsule filled with the composition to be deformed. Ina preferred embodiment, the inventive composition contains essentiallyno polyhydric alcohol. In other words, the composition does not containthe polyhydric alcohol at a content higher than 4% by weight, forinstance, when the composition is defined to be 100% by weight as awhole. Alternatively, the polyhydric alcohol content is up to 4% byweight, preferably up to 3% by weight, more preferably up to 2% byweight, even more preferably up to 1% by weight, and most preferably 0%by weight.

Advantageously, the content of the ethanol in the self-emulsifyingcomposition of the present invention is such that change in the qualityis not induced during the encapsulation, distribution or storage, anddenaturing of the capsule content is not induced either, and the ethanolcontent should not exceed the daily experientially allowable medicaldose. In a preferred embodiment, the inventive composition containsessentially no ethanol. In other words, the composition does not containthe ethanol at a content higher than 4% by weight, for instance, whenthe composition is defined to be 100% by weight as a whole.Alternatively, the ethanol content is up to 4% by weight, preferably upto 3% by weight, more preferably up to 2% by weight, even morepreferably up to 1% by weight, and most preferably 0% by weight.

When the ethanol and the polyhydric alcohol are added in thecomposition, the total content of the ethanol and the polyhydric alcoholis preferably not more than 4% by weight when the composition is definedto be 100% by weight as a whole. The total content of the ethanol andthe polyhydric alcohol in the composition is preferably up to 4% byweight, more preferably up to 3% by weight, still more preferably up to2% by weight, even more preferably up to 1% by weight, and mostpreferably 0% by weight.

Preferable ethanol concentration may be determined based on the ω3 PUFAconcentration of the self-emulsifying composition and the daily dose ofthe self-emulsifying composition. When the self-emulsifying compositionof the present invention is orally administered at a daily dose of 1800mg in terms of ω3 PUFA, and a preparation containing the ω3 PUFA, forexample, at 75% by weight is prepared, the ethanol dose will not exceed3.26 mg which is daily maximum dose described in the “Dictionary ofPharmaceutical Additives” when the ethanol concentration is up to 0.135%by weight.

For the self-emulsifying composition of the present invention containingsuch ω3 PUFA and emulsifying agent as described above, a preferredembodiment is the combination containing 1) EPA-E and/or DHA-E, 2)water, and 3) a polyoxyethylene sorbitan fatty acid ester as anemulsifier. Another preferred embodiment is the combination of 1) EPA-Eand/or DHA-E, 2) water, and 3) at least two emulsifiers selected fromthe group consisting of a sorbitan fatty acid ester, a glycerin fattyacid ester and a polyoxyethylene castor oil.

Another preferred embodiment is the combination of 1) EPA-E and/orDHA-E, 2) water, 3) a polyoxyethylene sorbitan fatty acid ester as anemulsifier, and 4) at least one emulsifier selected from the groupconsisting of a sorbitan fatty acid ester, a glycerin fatty acid esterand a polyoxyethylene castor oil. Yet another preferred embodiment isthe combination of 1) EPA-E and/or DHA-E, 2) water, 3) a polyoxyethylenesorbitan fatty acid ester as an emulsifier, and 4) at least twoemulsifiers selected from the group consisting of a sorbitan fatty acidester, a glycerin fatty acid ester and a polyoxyethylene castor oil.

In each of such self-emulsifying compositions, the content of the EPA-Eand/or DHA-E 1) is 70 to 90% by weight, the content of the water 2) is0.5 to 6% by weight, and the content of the emulsifier or emulsifiers 3)is 1 to 29% by weight when the relevant composition is defined to be100% by weight as a whole.

The self-emulsifying composition of the present invention may beencapsulated in a capsule. The capsule selected may be a hard capsule ora soft capsule, and preferably, the capsule used is a soft capsule. Thesoft capsule is not particularly limited in shape, and preferably, thesoft capsule is a rotary die type soft capsule or a seamless capsule.

In the soft capsule of the present invention, the capsule film is notnecessarily limited for its composition, and exemplary main ingredientsinclude gelatin, carageenan, pectin, pullulan, sodium arginate, starch,hypromellose, hydroxypropyl cellulose, and other known ingredients. Thepreferred is gelatin, and the type of gelatin used is not particularlylimited. Exemplary gelatins include acid-treated gelatin, alkali-treatedgelatin, amphoteric gelatin, chemically modified gelatin, and otherknown gelatins, which may be used alone or in combination of two ormore. The gelatin used is preferably an acid-treated gelatin oralkali-treated gelatin. The source of the gelatin is not necessarilylimited, and the gelatin used may be the one from cattle bone, cattleskin, pig bone, pig skin, fish scale, or fish skin, and preferably, theone from cattle bone, cattle skin, pig bone, or pig skin.

The “gelatin” used may be the one normally used in the production of asoft capsule, for example, medical gelatin (gelatin and purifiedgelatin) defined in The Japanese Pharmacopoeia 16th edition. The gelatinmay also be a combination of two or more types, and the capsule film mayalso contain other components such as a plasticizing agent.

The “plasticizing agent” added to the capsule film may be the onenormally used in the production of a soft capsule, with preferredexamples including a polyhydric alcohol such as glycerin (for example,concentrated glycerin), ethylene glycol, polyethylene glycol, propyleneglycol, or polypropylene glycol, and a sugar alcohol such as sorbitol,mannitol, or xylitol. These plasticizing agents may be used incombination of two or more. Particularly preferred are glycerin andsorbitol. Also preferred is a combination of glycerin and sorbitol, andin this case, the glycerin and the sorbitol may be used at a weightratio in the range of 1:5 to 5:1, and more preferably 1:3 to 3:1.

In the soft capsule preparation, and in particular, in the seamlesscapsule of the present invention, the capsule film solution preferablycontains the gelatin and the plasticizing agent at a weight ratio in therange of 10:1 to 1:10, and more preferably of 10:1 to 1:1.

The weight ratio between the capsule film solution and the capsulecontent is typically 10:1 to 1:10, and preferably 3:1 to 1:10.

If desired, the capsule film may also contain various additives commonlyused in the capsule film. Exemplary such additives include amino acids,citric acid, glycerin, sorbitol, trehalose, and other plasticizingagents, antiseptic, dye, titanium oxide, and other colorants, andorganic acids.

The composition for the capsule film may be prepared by dissolvinggelatin, the plasticizing agent, and the optional additives in water atroom temperature or at an elevated temperature.

A capsulated self-emulsifying preparation having the self-emulsifyingcomposition of the present invention as its liquid content preferablyhas high hardness immediately after the production, and this hardness ispreferably maintained during the storage. Loss of the hardness isunfavorable in view of the quality because the loss of the hardness doesnot only result in the deformation but also fragileness and breakage ofthe capsule and bleeding of the content. Softening of the capsule can bedetected by measuring the hardness with a common hardness tester.

The capsulated self-emulsifying preparation of the present invention hasthe hardness immediately after the production of at least 18 kgf,preferably at least 20 kgf, and more preferably at least 22 kgf. It isdesirable that the hardness of the preparation does not substantiallydecrease, or not decrease by 6 kgf or more when the preparation isstored in a tightly sealed aluminum package at 40° C. for 1 weekcompared with the hardness immediately after the production. Preferably,the inventive preparation has a hardness of at least 10 kgf, morepreferably of at least 15 kgf, and even more preferably of at least 20kgf after the storage at 40° C. for 1 week.

With the hardness immediately after the production being assumed to be100%, at least 60%, preferably at least 70%, more preferably at least80%, and most preferably at least 90% thereof is exhibited (maintained)after the storage in a tightly sealed aluminum package at 40° C. for 1week.

The dose and dosage period of the ω3 PUFA used in the self-emulsifyingcomposition of the present invention are made sufficient for realizingthe intended action, and can be adequately adjusted depending on theadministration route, frequency of administration per day, seriousnessof the symptoms, body weight, age, and other factors.

In the case of oral administration, the composition is administered oneto three times a day at an EPA-E dose, for instance, of 0.1 to 5 g/day,preferably of 0.2 to 3 g/day, more preferably of 0.3 to 3 g/day, stillmore preferably of 0.5 to 3 g/day, and even more preferably of 0.9 to 3g/day. The administration may be conducted one time at the entire doseor several times at divided doses as required. The frequency ofadministration per day is preferably one time a day or two or threetimes a day. In the case of one time administration per day, one to tencapsules, preferably one to eight capsules, more preferably one to sixcapsules, still more preferably one to four capsules, and even morepreferably one to three capsules as soft capsules each containing 1 g ofEPA-E, for instance, can be administered. Soft capsules each containing1 g of EPA-E may be combined with soft capsules each containing 0.5 g ofthe ester so as to administer the composition at an EPA-E dose of 0.5 g,1.5 g, 2.5 g, 3.5 g, 4.5 g or 5.5 g/administration.

While administration of EPA-E during to after meals is deemedpreferable, and administration immediately after meals (within 30minutes after meals) more preferable, because the absorption of EPA-E isinfluenced by diet, the self-emulsifying composition of the presentinvention has an excellent absorbability under fasting, and therefore,it exerts the intended effects even when administered at a timing otherthan during, after or immediately after meals, for example, before orimmediately before meals, between meals, or at bedtime; whenadministered to patients with reduced absorption ability of theintestinal tract (for example, elderly, patients of intestinal disease,patients after intestinal surgery, terminal cancer patients, or patientstaking a lipase inhibitor); or when administered at a reduced dose.

The self-emulsifying composition of the present invention is preferablycharacterized in that the time until the maximum blood concentration isattained after the oral administration is comparable to or shorter thanthat found for the ω3 PUFA stock solution. Otherwise, the inventivecomposition is preferably characterized in that the maximum bloodconcentration is higher than that found for the ω3 PUFA stock solution.In addition, the inventive composition is preferably characterized inthat the blood concentration two hours after the administration, thearea under the blood concentration vs time curve from zero to two hoursafter the administration, and/or the area under the blood concentrationvs time curve from zero to 72 hours after the administration iscomparable to or higher than that found for the ω3 PUFA stock solution.More preferably, the self-emulsifying composition of the presentinvention is characterized in that the time until the maximum bloodconcentration is attained is short, the maximum blood concentration ishigh, and both the blood concentration two hours after theadministration and the area under the blood concentration vs time curvefrom zero to two hours and/or from zero to 72 hours after theadministration are high as compared with those for the ω3 PUFA stocksolution, respectively.

Such pharmacokinetics as above can be confirmed with dogs, monkeys orother animals, and preferably by examination on humans.

In a pharmacokinetic study conducted by orally administering theself-emulsifying composition to male beagles as fasted for at least 18hours at an ω3 PUFA dose of 600 mg, the maximum ω3 PUFA bloodconcentration is, for instance, preferably at least 50 μg/mL, morepreferably at least 60 μg/mL, and even more preferably at least 70μg/mL, as calculated with correction by subtraction of the blood ω3polyunsaturated fatty acid concentration before the administration ofthe composition. The area under the blood ω3 PUFA concentration vs timecurve from zero to two hours after the administration is preferably atleast 50 μg/mL·hr, more preferably at least 60 μg/mL·hr, and even morepreferably at least 70 μg/mL·hr. The combination of the ranges of themaximum ω3 PUFA blood concentration and the area under the blood ω3 PUFAconcentration vs time curve is preferably a combination of the range ofat least 50 μg/mL and the range of at least 50 μg/mL·hr, more preferablya combination of the range of at least 60 μg/mL and the range of atleast 60 μg/mL·hr, and even more preferably a combination of the rangeof at least 70 μg/mL and the range of at least 70 μg/mL·hr.

In a pharmacokinetic study conducted by orally administering theself-emulsifying composition to male crab-eating macaques as fasted forat least 12 hours at an ω3 PUFA dose of 45 mg/kg body weight, themaximum ω3 PUFA blood concentration is preferably at least 50 μg/mL, andmore preferably at least 70 μg/mL, as calculated with correction bysubtraction of the blood ω3 polyunsaturated fatty acid concentrationbefore the administration of the composition. The area under the bloodω3 PUFA concentration vs time curve from zero to 12 hours after theadministration is preferably at least 400 μg/mL·hr, and more preferablyat least 500 μg/mL. The combination of the ranges of the maximum ω3 PUFAblood concentration and the area under the blood ω3 PUFA concentrationvs time curve as above is preferably a combination of the range of atleast 50 μg/mL and the range of at least 400 μg/mL·hr, and morepreferably a combination of the range of at least 70 μg/mL and the rangeof at least 500 μg/mL·hr.

In a pharmacokinetic study conducted by orally administering theself-emulsifying composition to humans at such a timing as before meals,immediately after meals or after meals at an ω3 PUFA or EPA dose of 1800mg, the maximum ω3 PUFA blood concentration is preferably at least 50μg/mL, more preferably at least 100 μg/mL, still more preferably atleast 150 μg/mL, even more preferably at least 200 μg/mL, and mostpreferably at least 300 μg/mL, as calculated with correction bysubtraction of the blood ω3 polyunsaturated fatty acid concentrationbefore the administration of the composition. Alternatively, the maximumω3 PUFA blood concentration is preferably 10 to 1000 μg/mL, morepreferably 20 to 500 μg/mL, still more preferably 40 to 300 μg/mL, evenmore preferably 50 to 150 μg/mL, and most preferably 50 to 100 μg/mL.The area under the blood ω3 PUFA concentration vs time curve from zeroto 72 hours after the administration is preferably at least 500μg/mL·hr, more preferably at least 1000 μg/mL·hr, still more preferablyat least 1500 μg/mL·hr, even more preferably at least 2000 μg/mL·hr, andmost preferably at least 3000 μg/mL·hr. Alternatively, the area underthe blood ω3 PUFA concentration vs time curve as above is preferably 500to 4500 μg/mL·hr, more preferably 600 to 3000 μg/mL·hr, still morepreferably 700 to 2500 μg/mL·hr, even more preferably 800 to 2000μg/mL·hr, and most preferably 1000 to 1500 μg/mL·hr. The time until themaximum plasma concentration is attained is preferably up to 6 hours,more preferably up to 5 hours, still more preferably up to 3 hours, evenmore preferably up to 1 hour, and most preferably less than one hour.Alternatively, the time until the maximum plasma concentration isattained is preferably 0.5 to 10 hours, more preferably 1 to 8 hours,still more preferably 1.5 to 7 hours, even more preferably 2 to 5 hours,and most preferably 2.5 to 4 hours. The plasma elimination half-life ispreferably at least 10 hours, more preferably at least 20 hours, stillmore preferably at least 30 hours, even more preferably at least 40hours, and most preferably at least 50 hours. Alternatively, the plasmaelimination half-life is preferably 0 to 150 hours, more preferably 10to 120 hours, still more preferably 30 to 100 hours, even morepreferably 25 to 75 hours, and most preferably 25 to 50 hours.

In a pharmacokinetic study conducted by orally administering theself-emulsifying composition to humans at such a timing as before meals,immediately after meals or after meals at an ω3 PUFA or EPA dose of 3600mg, the maximum ω3 PUFA blood concentration is preferably at least 50μg/mL, more preferably at least 100 μg/mL, still more preferably atleast 150 μg/mL, even more preferably at least 200 μg/mL, and mostpreferably at least 300 μg/mL, as calculated with correction bysubtraction of the blood ω3 polyunsaturated fatty acid concentrationbefore the administration of the composition. Alternatively, the maximumω3 PUFA blood concentration is preferably 10 to 1000 μg/mL, morepreferably 20 to 500 μg/mL, still more preferably 50 to 400 μg/mL, evenmore preferably 100 to 300 μg/mL, and most preferably 150 to 200 μg/mL.The area under the blood ω3 PUFA concentration vs time curve from zeroto 72 hours after the administration is preferably at least 500μg/mL·hr, more preferably at least 1000 μg/mL·hr, still more preferablyat least 1500 μg/mL·hr, even more preferably at least 2000 μg/mL·hr, andmost preferably at least 3000 μg/mL·hr. Alternatively, the area underthe blood ω3 PUFA concentration vs time curve as above is preferably 500to 5000 μg/mL·hr, more preferably 1000 to 4700 μg/mL·hr, still morepreferably 1500 to 4500 μg/mL·hr, even more preferably 2000 to 4000μg/mL·hr, and most preferably 2500 to 3500 μg/mL·hr. The time until themaximum plasma concentration is attained is preferably up to 6 hours,more preferably up to 5 hours, still more preferably up to 3 hours, evenmore preferably up to 1 hour, and most preferably less than one hour.Alternatively, the time until the maximum plasma concentration isattained is preferably 0.5 to 10 hours, more preferably 1 to 8 hours,still more preferably 1.5 to 7 hours, even more preferably 2 to 6 hours,and most preferably 3 to 5 hours. The plasma elimination half-life ispreferably at least 10 hours, more preferably at least 20 hours, stillmore preferably at least 30 hours, even more preferably at least 40hours, and most preferably at least 50 hours. Alternatively, the plasmaelimination half-life is preferably 0 to 150 hours, more preferably 10to 120 hours, still more preferably 30 to 100 hours, even morepreferably 25 to 75 hours, and most preferably 25 to 50 hours.

In the case of a pharmacokinetic study with humans, the above-mentionednumerical ranges may also be replaced by those mentioned below. To bemore specific: In a study conducted by orally administering theself-emulsifying composition at such a timing as before, immediatelyafter or after meals at an EPA dose of 1800 mg, the maximum ω3 PUFAplasma concentration as calculated with correction by subtraction of theblood ω3 polyunsaturated fatty acid concentration before theadministration of the composition is not particularly limited, while itmay be specified to be: 10 to 50; 50 to 100; 100 to 150; 150 to 200; 200to 250; 250 to 300; 300 to 350; 350 to 400; 400 to 450; 450 to 500; 500to 600; 600 to 700; 700 to 800; 800 to 900; 900 to 1000; 10 to 30; 20 to40; 30 to 50; 40 to 60; 50 to 70; 60 to 80; 70 to 90; 80 to 100; 90 to110; 100 to 120; 110 to 130; 120 to 140; 130 to 150; 140 to 160; 150 to170; 160 to 180; 170 to 190; 180 to 200; 190 to 210; 200 to 220; 220 to240; 240 to 260; 260 to 280; 280 to 300; 10 to 20; 15 to 25; 20 to 30;25 to 35; 30 to 40; 35 to 45; 40 to 50; 45 to 55; 50 to 55; 53 to 58; 55to 60; 58 to 63; 60 to 65; 63 to 68; 65 to 70; 68 to 73; 70 to 75; 73 to78; 75 to 80; 78 to 83; 80 to 85; 83 to 88; 85 to 90; 88 to 93; 90 to95; 93 to 98; 95 to 100; 98 to 103; 100 to 105; 103 to 108; 105 to 110;108 to 113; 110 to 115; 113 to 118; 115 to 120; 118 to 123; 120 to 125;123 to 128; 125 to 130; 128 to 133; 130 to 135; 133 to 138; 135 to 140;138 to 143; 140 to 145; 143 to 148; 145 to 150; 150 to 160; 155 to 165;160 to 170; 165 to 175; 170 to 180; 175 to 185; 180 to 190; 185 to 195;190 to 200; 195 to 205; 200 to 210; 205 to 215; 210 to 220; 215 to 225;220 to 230; 225 to 235; 230 to 240; 235 to 245; or 240 to 250 μg/mL. Ina study conducted by administering the self-emulsifying composition atsuch a timing as before, immediately after or after meals at an EPA doseof 3600 mg, the maximum ω3 PUFA plasma concentration may be specified tobe: 10 to 50; 50 to 100; 100 to 150; 150 to 200; 200 to 250; 250 to 300;300 to 350; 350 to 400; 400 to 450; 450 to 500; 500 to 600; 600 to 700;700 to 800; 800 to 900; 900 to 1000; 10 to 30; 20 to 40; 30 to 50; 40 to60; 50 to 70; 60 to 80; 70 to 90; 80 to 100; 90 to 110; 100 to 120; 110to 130; 120 to 140; 130 to 150; 140 to 160; 150 to 170; 160 to 180; 170to 190; 180 to 200; 190 to 210; 200 to 220; 220 to 240; 240 to 260; 260to 280; 280 to 300; 10 to 20; 15 to 25; 20 to 30; 25 to 35; 30 to 40; 35to 45; 40 to 50; 45 to 55; 50 to 55; 53 to 58; 55 to 60; 58 to 63; 60 to65; 63 to 68; 65 to 70; 68 to 73; 70 to 75; 73 to 78; 75 to 80; 78 to83; 80 to 85; 83 to 88; 85 to 90; 88 to 93; 90 to 95; 93 to 98; 95 to100; 98 to 103; 100 to 105; 103 to 108; 105 to 110; 108 to 113; 110 to115; 113 to 118; 115 to 120; 118 to 123; 120 to 125; 123 to 128; 125 to130; 128 to 133; 130 to 135; 133 to 138; 135 to 140; 138 to 143; 140 to145; 143 to 148; 145 to 150; 150 to 160; 155 to 165; 160 to 170; 165 to175; 170 to 180; 175 to 185; 180 to 190; 185 to 195; 190 to 200; 195 to205; 200 to 210; 205 to 215; 210 to 220; 215 to 225; 220 to 230; 225 to235; 230 to 240; 235 to 245; or 240 to 250 μg/mL.

The area under the blood ω3 PUFA concentration vs time curve from zeroto 72 hours after the administration in a study conducted byadministering the self-emulsifying composition at such a timing asbefore, immediately after or after meals at an EPA dose of 1800 mg maybe specified to be: 500 to 1500; 1000 to 2000; 1500 to 2500; 2000 to3000; 2500 to 3500; 3000 to 4000; 500 to 1000; 750 to 1250; 1000 to1500; 1250 to 1750; 1500 to 2000; 1750 to 2250; 2000 to 2500; 2250 to2750; 2500 to 3000; 2750 to 3250; 3000 to 3500; 3250 to 3750; 3500 to4000; 3750 to 4250; 4000 to 4500; 4250 to 4750; 4500 to 5000; 500 to700; 600 to 800; 700 to 900; 800 to 1000; 900 to 1100; 1000 to 1200;1100 to 1300; 1200 to 1400; 1300 to 1500; 1400 to 1600; 1500 to 1700;1600 to 1800; 1700 to 1900; 1800 to 2000; 1900 to 2100; 2000 to 2200;2100 to 2300; 2200 to 2400; 2300 to 2500; 2400 to 2600; 2500 to 2700;2600 to 2800; 2700 to 2900; 2800 to 3000; 2900 to 3100; 3000 to 3200;3100 to 3300; 3200 to 3400; 3300 to 3500; 3400 to 3600; 3500 to 3700;3600 to 3800; 3700 to 3900; 3800 to 4000; 3900 to 4100; 4000 to 4200;4100 to 4300; 4200 to 4400; 4300 to 4500; 500 to 600; 550 to 650; 600 to700; 650 to 750; 700 to 800; 750 to 850; 800 to 900; 850 to 950; 900 to1000; 950 to 1050; 1000 to 1100; 1050 to 1150; 1100 to 1200; 1150 to1250; 1200 to 1300; 1250 to 1350; 1300 to 1400; 1350 to 1450; 1400 to1500; 1450 to 1550; 1500 to 1600; 1550 to 1650; 1600 to 1700; 1650 to1750; 1700 to 1800; 1750 to 1850; 1800 to 1900; 1850 to 1950; 1900 to2000; 1950 to 2050; 2000 to 2100; 2050 to 2150; 2100 to 2200; 2150 to2250; 2200 to 2300; 2250 to 2350; 2300 to 2400; 2350 to 2450; 2400 to2500; 2450 to 2550; 2500 to 2600; 2550 to 2650; 2600 to 2700; 2650 to2750; 2700 to 2800; 2750 to 2850; 2800 to 2900; 2850 to 2950; 2900 to3000; 2950 to 3050; 3000 to 3100; 3150 to 3250; 3200 to 3300; 3250 to3350; 3300 to 3400; 3350 to 3450; 3400 to 3500; 3500 to 3600; 3600 to3700; 3700 to 3800; 3800 to 3900; 3900 to 4000; 4000 to 4100; 4100 to4200; 4200 to 4300; 4300 to 4400; or 4400 to 4500 μg/mL hr. In a studyconducted by administering the self-emulsifying composition at such atiming as before, immediately after or after meals at an EPA dose of3600 mg, the area under the blood ω3 PUFA concentration vs time curve asabove may be specified to be: 500 to 1500; 1000 to 2000; 1500 to 2500;2000 to 3000; 2500 to 3500; 3000 to 4000; 500 to 1000; 750 to 1250; 1000to 1500; 1250 to 1750; 1500 to 2000; 1750 to 2250; 2000 to 2500; 2250 to2750; 2500 to 3000; 2750 to 3250; 3000 to 3500; 3250 to 3750; 3500 to4000; 3750 to 4250; 4000 to 4500; 4250 to 4750; 4500 to 5000; 500 to700; 600 to 800; 700 to 900; 800 to 1000; 900 to 1100; 1000 to 1200;1100 to 1300; 1200 to 1400; 1300 to 1500; 1400 to 1600; 1500 to 1700;1600 to 1800; 1700 to 1900; 1800 to 2000; 1900 to 2100; 2000 to 2200;2100 to 2300; 2200 to 2400; 2300 to 2500; 2400 to 2600; 2500 to 2700;2600 to 2800; 2700 to 2900; 2800 to 3000; 2900 to 3100; 3000 to 3200;3100 to 3300; 3200 to 3400; 3300 to 3500; 3400 to 3600; 3500 to 3700;3600 to 3800; 3700 to 3900; 3800 to 4000; 3900 to 4100; 4000 to 4200;4100 to 4300; 4200 to 4400; 4300 to 4500; 500 to 600; 550 to 650; 600 to700; 650 to 750; 700 to 800; 750 to 850; 800 to 900; 850 to 950; 900 to1000; 950 to 1050; 1000 to 1100; 1050 to 1150; 1100 to 1200; 1150 to1250; 1200 to 1300; 1250 to 1350; 1300 to 1400; 1350 to 1450; 1400 to1500; 1450 to 1550; 1500 to 1600; 1550 to 1650; 1600 to 1700; 1650 to1750; 1700 to 1800; 1750 to 1850; 1800 to 1900; 1850 to 1950; 1900 to2000; 1950 to 2050; 2000 to 2100; 2050 to 2150; 2100 to 2200; 2150 to2250; 2200 to 2300; 2250 to 2350; 2300 to 2400; 2350 to 2450; 2400 to2500; 2450 to 2550; 2500 to 2600; 2550 to 2650; 2600 to 2700; 2650 to2750; 2700 to 2800; 2750 to 2850; 2800 to 2900; 2850 to 2950; 2900 to3000; 2950 to 3050; 3000 to 3100; 3150 to 3250; 3200 to 3300; 3250 to3350; 3300 to 3400; 3350 to 3450; 3400 to 3500; 3500 to 3600; 3600 to3700; 3700 to 3800; 3800 to 3900; 3900 to 4000; 4000 to 4100; 4100 to4200; 4200 to 4300; 4300 to 4400; or 4400 to 4500 μg/mL·hr.

The time until the maximum plasma concentration is attained in a studyconducted by administering the self-emulsifying composition at such atiming as before, immediately after or after meals at an EPA dose of1800 mg or 3600 mg may be specified to be: 0 to 2; 1 to 3; 2 to 4; 3 to5; 4 to 6; 5 to 7; 6 to 8; 7 to 9; 8 to 10; 0 to 1; 0.5 to 1.5; 1 to 2;1.5 to 2.5; 2 to 3; 2.5 to 3.5; 3 to 4; 3.5 to 4.5; 4 to 5; 4.5 to 5.5;5 to 6; 5.5 to 6.5; 6 to 7; 6.5 to 7.5; 7 to 8; 7.5 to 8.5; 8 to 9; 8.5to 9.5; 9 to 10; 0 to 0.5; 0.3 to 0.8; 0.5 to 1; 0.8 to 1.3; 1 to 1.5;1.3 to 1.8; 1.5 to 2; 1.8 to 2.3; 2 to 2.5; 2.3 to 2.8; 2.5 to 3; 2.8 to3.3; 3 to 3.5; 3.3 to 3.8; 3.5 to 4; 3.8 to 4.3; 4 to 4.5; 4.3 to 4.8;4.5 to 5; 4.8 to 5.3; 5 to 5.5; 5.3 to 5.8; 5.5 to 6; 5.8 to 6.3; 6 to6.5; 6.3 to 6.8; 6.5 to 7; 6.8 to 7.3; 7 to 7.5; 7.3 to 7.8; 7.5 to 8;7.8 to 8.3; 8 to 8.5; 8.3 to 8.8; 8.5 to 9; 8.8 to 9.3; 9 to 9.5; 9.3 to9.8; or 9.5 to 10 hours.

The plasma elimination half-life in a study conducted by administeringthe self-emulsifying composition at such a timing as before, immediatelyafter or after meals at an EPA dose of 1800 mg or 3600 mg may bespecified to be: 0 to 50; 25 to 75; 50 to 100; 75 to 125; 100 to 150;125 to 175; 150 to 200; 0 to 20; 10 to 30; 20 to 40; 30 to 50; 40 to 60;50 to 70; 60 to 80; 70 to 90; 80 to 100; 90 to 110; 100 to 120; 110 to130; 120 to 140; 130 to 150; 0 to 10; 5 to 15; 10 to 20; 15 to 25; 20 to30; 25 to 35; 30 to 40; 35 to 45; 40 to 50; 45 to 55; 50 to 60; 55 to65; 60 to 70; 65 to 75; 70 to 80; 75 to 85; 80 to 90; 85 to 95; 90 to100; 95 to 105; 100 to 110; 105 to 115; or 110 to 120 hours.

The present invention may be defined by a combination of two or moreselected from among the maximum ω3 PUFA plasma concentration, the areaunder the blood ω3 PUFA concentration vs time curve from zero to 72hours after the administration, the time until the maximum plasmaconcentration is attained, and the plasma elimination half-life.

The self-emulsifying composition of the present invention may alsocontain additives such as an emulsification aid, stabilizer, antiseptic,surfactant, and antioxidant. Exemplary emulsification aids include fattyacids containing 12 to 22 carbon atoms such as stearic acid, oleic acid,linoleic acid, palmitic acid, linolenic acid, and myristic acid andtheir salts. Exemplary stabilizers include phosphatidic acid, ascorbicacid, glycerin, and cetanols, and exemplary antiseptics include ethylparaoxybenzoate and propyl paraoxybenzoate. Exemplary antioxidantsinclude oil-soluble antioxidants such as butylated hydroxy toluene,butylated hydroxy anisole, propyl gallate, propyl gallate,pharmaceutically acceptable quinone, astaxanthin, and α-tocopherol.

In addition, an adequate carrier or vehicle, a colorant, a flavor, andoptionally, a vegetable oil and an additive such as non-toxic organicsolvent or non-toxic solubilizing agent, emulsifier, suspending agent(for example, Tween 80 and gum arabic solution), isotonic agent, pHadjusting agent, stabilizer, corrective, flavoring agent, preservative,antioxidant, or absorption promoter commonly used in the art may beadequately combined with the inventive composition to prepare anappropriate pharmaceutical preparation.

More specifically, since the ω3 PUFA is highly unsaturated, effectiveamount of an oil-soluble antioxidant, for example, at least one memberselected from butylated hydroxytoluene, butylated hydroxyanisole, propylgallate, propyl gallate, pharmaceutically acceptable quinone,astaxanthin, and α-tocopherol is preferably incorporated in thecomposition.

Since the self-emulsifying composition of the present invention is alsoused for pharmaceutical application, it preferably has good appearance,self-emulsifying property, composition dispersibility, emulsionstability, and storage stability. The appearance of the self-emulsifyingcomposition is such that the composition is not separated, clouded,solidified, or precipitated, but transparent. The composition havingpoor appearance may be pharmaceutically unsuitable, and such compositionmay be insufficient in required performance such as self-emulsifyingproperty.

With regard to the storage temperature, the self-emulsifying compositionand the preparation prepared by encapsulating such composition ispreferably transparent at both low temperature and high temperature inview of its use in cold district or hot environment.

In the case of the self-emulsifying composition having goodself-emulsifying property, good dispersibility of the composition, andhigh emulsion stability, the composition rapidly disperses upon contactwith water to form a microemulsion having adequate emulsion dropletdiameter. Absorbability of an oil such as EPA-E is related to the sizeof the emulsion droplet diameter, and degree of the absorbability uponadministration to the animal can be estimated by measuring the emulsiondroplet diameter.

In the present invention, the “mean droplet diameter” is the value ofvolume mean diameter among droplets of the emulsified compositionmeasured by using a particle size analyzer (for example, Nanotoracmanufactured by Nikkiso Co., Ltd.) with water being used for thedispersion medium according to standard measurement method (for example,set zero time of 30 seconds, measurement time of 30 seconds, average ofthree measurements). The mean droplet diameter when the self-emulsifyingcomposition of the present invention is dispersed in water or the likeis not particularly limited as long as it is up to 2 μm, and the producthas good emulsion dispersibility, good emulsion stability, or goodabsorbability, and the mean droplet diameter is typically up to 1.5 μm,more preferably up to 1.0 μm, still more preferably up to 0.5 μm, andmost preferably up to 0.3 μm.

The self-emulsifying composition of the present invention may be used bycombining with a second effective component. The second effectivecomponent may be any component adequately selected depending on theintended type and severity of the disease as long as it does notadversely affect the merits of the ω3 PUFAs. Exemplary such secondeffective components include therapeutic agents for hyperlipidemia,antihypertensives, antidiabetics, antioxidants, blood flow improvingagents, bile acid derivatives, therapeutic agents for NAFLD and NASH, aswell as progression suppressants and therapeutic agents for cognitiveimpairment.

Examples of a favorable second effective component include suchtherapeutic agents for hyperlipidemia as polyene phosphatidyl choline,unsaponifiable matter in soybean oil (soysterol), gamma orizanol,riboflavin butyrate, dextran sulfate sodium sulfur 18, pantethine, andelastase. Also included are statins such as pravastatin, simbastatin,atorvastatin, fluvastatin, pitavastatin, rosuvastatin and cerivastatin;fibrates such as simfibrate, clofibrate, clinofibrate, bezafibrate andfenofibrate; lipolytic enzyme inhibitors such as orlistat andcetilistat; resins such as cholestyramine and cholestyramide; andezetimibe.

Exemplary antihypertensives include: angiotensin II receptor antagonistssuch as irbesartan, olmesartan medoxomil, candesartan cilexetil,telmisartan, valsartan, and losartan potassium; angiotensin convertingenzyme inhibitors such as alacepril, imidapril hydrochloride, enalaprilmaleate, captopril, quinapril hydrochloride, cilazapril hydrate,temocapril hydrochloride, delapril hydrochloride, trandolapril,benazepril hydrochloride, perindopril, and lisinopril hydrate; calciumantagonists such as azelnidipine, amlodipine besylate, aranidipine,efonidipine hydrochloride, cilnidipine, nicardipine hydrochloride,nifedipine, nimodipine, nitrendipine, nilvadipine, barnidipinehydrochloride, felodipine, benidipine, and manidipin; α-receptorblockers such as tolazoline and phentolamine; β-receptor blockers suchas atenolol, metoprolol, acebutolol, propranolol, pindolol, carvedilol,and labetalol hydrochloride; α-receptor stimulants such as clonidine andmethyldopa; and diuretics such as eplerenone, hydrochlorothiazide andfurosemide.

Exemplary antidiabetics include: α-glucosidase inhibitors such asacarbose, voglibose and miglitol; sulfonylurea hypoglycemic agents suchas gliclazide, glibenclamide, glimepiride and tolbutamide; short-actinginsulin secretagogues such as nateglinide and mitiglinide; biguanidehypoglycemic agents such as metformin hydrochloride and buforminhydrochloride; dipeptidyl phosphatase-4 inhibitors such as sitagliptin,vildagliptin, alogliptin, linagliptin, teneligliptin, anagliptin andsaxagliptin; thiazolidines such as pioglitazone hydrochloride androsiglitazone maleate; glucagon-like peptide 1 derivatives such asexenatide and liraglutide; and sodium-glucose cotransporter 2 inhibitorssuch as ipragliflozin, dapagliflozin, luseogliflozin, tofogliflozin,canagliflozin and empagliflozin.

Exemplary antioxidants include such vitamins as ascorbic acid (vitaminC), tocopherol (vitamin E) and tocopherol nicotinate ester,N-acetylcysteine, and probucol.

Exemplary blood flow improving agents include cilostazol, ticlopidinehydrochloride, alprostadil, limaprost, beraprost sodium, sarpogrelatehydrochloride, argatroban, naftidrofuryl, isoxsuprine hydrochloride,batroxobin, dihydroergotoxine mesylate, tolazoline hydrochloride,hepronicate, and shimotsuto extract.

Exemplary bile acid derivatives include ursodeoxycholic acid,chenodeoxycholic acid, bile powder, deoxycholic acid, cholic acid, bileextract, bear bile, oriental bezoar, and dehydrocholic acid. Favorableexamples are biotin (vitamin B7), cyanocobalamin (vitamin B12),pantothenic acid (vitamin B5), folic acid (vitamin B9), thiamine(vitamin B1), vitamin A, vitamin D, vitamin K, tyrosine, pyridoxine(vitamin B6), branched amino acids such as leucine, isoleucine andvaline, calcium, iron, zinc, copper, magnesium, and the like. Alsofavorable are such ingredients of foods for specified health use andfoods with nutrient function claims as soybean proteins, chitosan, lowmolecular-weight sodium alginate, dietary fiber derived from psylliumseed husks, soybean peptides bound to phospholipids, plant sterolesters, plant stanol esters, diacylglycerol, globin proteolysisproducts, and tea catechin.

Exemplary therapeutic agents for NAFLD and NASH include the statins suchas pravastatin, simbastatin, atorvastatin, fluvastatin, pitavastatin,rosuvastatin and cerivastatin; the angiotensin II receptor antagonistssuch as irbesartan, olmesartan medoxomil, candesartan lexetil,telmisartan, valsartan, and losartan potassium; the biguanidehypoglycemic agents such as metformin hydrochloride and buforminhydrochloride; and the thiazolidines such as pioglizone hydrochlorideand rosiglitazone maleate as mentioned above, as well as aspirin andfarnesoid X receptor (hereafter abbreviated as FXR) ligands such asursodeoxycholic acid, chenodeoxycholic acid and obeticholic acid.

Exemplary progression suppressants and therapeutic agents for cognitiveimpairment include acetylcholineesterase inhibitors such as donepezilhydrochloride and galantamine hydrobromide; NMDA receptor inhibitorssuch as memantine hydrochloride; antiplatelets such as aspirin,clopidogrel sulfate, cilostazol, and ticlopidine hydrochloride; andfactor Xa inhibitors such as rivaroxaban and apixaban. In addition, thetherapeutic agents for hyperlipidemia, antihypertensives, antidiabetics,antioxidants and blood flow improving agents as mentioned above are alsousable as progression suppressants and therapeutic agents for cognitiveimpairment.

To realize pharmacological actions of the ω3 PUFA, the self-emulsifyingcomposition of the present invention preferably has at least one meritselected from good appearance, good self-emulsifying property, highcomposition dispersibility, high emulsion stability, high storagestability (including the stability at low and high temperatures), highabsorbability, in particular high absorbability and high absorptionspeed under fasting conditions, and convenience in taking thepreparation or compliance.

The self-emulsifying composition of the present invention is welladapted for use as a therapeutic agent for treating various diseases ofanimals, mammals in particular, that is to say, is usable as, forinstance, therapeutic agent for dyslipidemia (hypercholesterolemia, LDLhypercholesterolemia, non-HDL hypercholesterolemia, VLDLhypercholesterolemia, HDL hypocholesterolemia, hypertriglyceridemia, apoB hyperlipoproteinemia, apo A-I hypolipoproteinemia, and so forth),therapeutic agent for postprandial hypertriglyceridemia,anti-arteriosclerotic, platelet aggregation suppressant, therapeuticagent for peripheral circulatory insufficiency, prophylactic agent forcardiovascular events, therapeutic agent for inflammatory disease(NAFLD, NASH, and so forth), progression suppressant and therapeuticagent for cognitive impairment (dementia of the Alzheimer's type,cerebrovascular dementia, mixed type of dementia, and so forth),anticancer agent, and therapeutic agent for central disease (depression,depressive condition, obsessive-compulsive disorder, social anxietydisorder, panic disorder, and so forth). In the treatment of thediseases as above, the inventive self-emulsifying composition is notparticularly limited in frequency of administration per day, and ispreferably administered one time a day at the entire daily dose or twoor three times a day at divided doses, with one or two timeadministration per day being more preferable and one time administrationper day most preferable.

The self-emulsifying composition of the present invention isparticularly effective for the amelioration or treatment of dyslipidemiaand postprandial hypertriglyceridemia, and the prevention of theirrecurrence or progression to metabolic syndrome, cardiocerebrovascularevents, and ulcer or gangrene at a limb distal end. Exemplary mammalsinclude human, domestic animals such as cattle, horse, and pig, andcompanion animals such as dog, cat, rabbit, rat, and mouse, and thepreferred is human. More specifically, the self-emulsifying compositionof the present invention is anticipated to show ameliorating ortherapeutic effects for dyslipidemia and postprandialhypertriglyceridemia in patients with dyslipidemia suffering fromincrease in the blood lipid, exhibiting insulin resistance or sufferingfrom increase in the blood pressure, such as metabolic syndromepatients.

EXAMPLES

Next, the present invention is described in further detail by referringto the following Examples and Comparative Examples which by no meanslimit the scope of the invention.

Example 1

In a vessel, 0.05 g of water, 0.95 g of polyoxyethylene (20) sorbitanoleate and 4 g of EPA-E as weighed were placed and sealed, and mixedunder heating to about 70° C. to thereby prepare a self-emulsifyingcomposition. The self-emulsifying composition thus prepared was sealedafter purging with nitrogen, and stored at room temperature until theevaluation was conducted. Formulation of the self-emulsifyingcomposition is shown in Table 1. In the table, the symbol “-” means thatthe component in question was not added or not measured.

Examples 2 through 8 and Comparative Examples 1 through 3

The self-emulsifying compositions of Examples 2 through 9 and thecompositions of Comparative Examples 1 through 3 were prepared andstored by repeating the method of Example 1 so that the compositionalratios were as shown in Table 1. Formulations of the self-emulsifyingcompositions are shown in Table 1.

Examples 9 through 17 and Comparative Examples 4 through 8

The self-emulsifying compositions of Examples 10 through 15 and thecompositions of Comparative Examples 4 through 8 were prepared andstored by repeating the method of Example 1 so that the compositionalratios were as shown in Table 2. Formulations of the self-emulsifyingcompositions are shown in Table 2.

Test Example 1 <Evaluation of Appearance>

The self-emulsifying compositions and the compositions of ComparativeExamples as produced by the above production method were allowed tostand at room temperature, and after about 1 hour, their appearance wasevaluated. When the composition was homogeneous due to its goodcompatibility, the composition was evaluated as “transparent.” Thecomposition was evaluated as “separated” when the separation wasobserved, and “cloudy” when opacity was observed.

The results are shown in Tables 1 and 2.

Test Example 2 <Evaluation of Self-Emulsifying Property>

The self-emulsifying compositions and the compositions of ComparativeExamples as produced by the above production method were evaluated forself-emulsifying property by adding 10 μL of each composition dropwiseto 5 mL of purified water or first fluid for dissolution test ofJapanese Pharmacopeia at 37° C. in the test tube. The composition whichspontaneously emulsified just by the dropwise addition was evaluated as“good,” and the case which did not become an emulsion just by thedropwise addition was evaluated as “poor.” The composition was thenlightly stirred under consistent condition, and other properties wereexamined. With regard to the dispersibility of the composition, thecomposition was evaluated as “good” when dispersed and as “poor” whenpartly left undispersed as a mass. With regard to the emulsionstability, the composition was evaluated as “good” when no oilseparation was observed, and as “poor” when oil separation was observed.It is to be noted that the compositions which were not evaluated as“transparent” in the appearance evaluation were not evaluated in suchproperties since inhomogeneous compositions were conceived to beinadequate for property evaluation.

The results are shown in Tables 1 and 2.

Test Example 3 <Evaluation of Emulsion Droplet Diameter> Conditions forthe measurement of mean droplet diameter and measurement results.

Using about 1.5 mL of the emulsified composition as obtained in TestExample 2, the mean droplet diameter (volume mean diameter) was measuredby a particle size analyzer (Nanotrac, manufactured by Nikkiso Co.,Ltd.) using water as a dispersion medium.

The results are shown in Tables 1 and 2.

Test Example 4 <Evaluation of the Appearance after Storage under SevereConditions>

The compositions which were evaluated as “transparent” in Test Example 1were allowed to stand and stored overnight (for about 12 hours) at 5° C.or 40° C. before their appearance was evaluated. When the compositionwas homogeneous due to its good compatibility, the composition wasevaluated as “transparent.” The composition was evaluated as “separated”when the separation was observed, and as “cloudy” when opacity wasobserved.

The results are shown in Tables 1 and 2. In the tables, the symbol “-”means that the component in question was not added or not measured.

TABLE 1 (1/2) Comp. Comp. Comp. Component Ex. 1 Ex. 2 Ex. 3 Ex. 4 Ex. 5Ex. 6 Ex. 7 Ex. 8 Ex. 1 Ex. 2 Ex. 3 Ethyl 80.0 84.0  80.0 75.0 84.0 80.0 80.0  76.0 80.0 80.0  94.0 eicosapentaenoate Purified water  1.01.0  1.0  2.0 1.0  1.0 0.5  4.0  0.0 8.0  1.0 Polyoxyethylene (20) 19.08.6 10.0 — 7.0 17.0 10.5  10.0 10.0 7.0  5.0 sorbitan oleatePolyoxyethylene (20) — — — 15.0 — — — — — — — sorbitan trioleateSorbitan — — — — 3.0 — 4.0  5.0  5.0 2.0 — monolaurate Sorbitan — 6.4 —— — — 1.0 — — — — sesquioleate Decaglyceryl — —  9.0 — — — — — — — —oleate Polyoxyl 35 — — —  8.0 4.0 — 4.0  5.0  5.0 3.0 — castor oilPropylene glycol — — — — 1.0 — — — — — — fatty acid ester Soybean — — —— —  2.0 — — — — — lecithin Total 100.00 100.00  100.00 100.00 100.00 100.00 100.00  100.00 100.00 100.00  100.00 (2/2) Comp. Comp. Comp. Ex.1 Ex. 2 Ex. 3 Ex. 4 Ex. 5 Ex. 6 Ex. 7 Ex. 8 Ex. 1 Ex. 2 Ex. 3 Test Ex. 1Appear- Trans- Trans- Trans- Trans- Trans- Trans- Trans- Trans- Separ-Separ- Separ- ance parent parent parent parent parent parent parentparent ated ated ated Test Ex. 2 Self- Good Good Good Good Good GoodGood Good Not Not Not emulsifying evaluated evaluated evaluated propertyComposition Good Good Good Good Good Good Good Good dispersibilityEmulsion Good Good Good Good Good Good Good Good stability Test Ex. 337° C. 0.23 0.41 0.19 0.19 0.22 0.25 0.21 0.20 Emulsion Purified dropletwater (μm) diameter 37° C. 0.29 0.29 0.87 0.24 0.18 0.27 0.18 0.23Japanese Pharmacopeia 1st liquid (μm) Test Ex. 4 Stored at Trans- Trans-Trans- Trans- Trans- Trans- Trans- Trans- Appearance 5° C. parent parentparent parent parent parent parent parent Stored at Trans- Trans- Trans-Trans- Trans- Trans- Trans- Trans- 40° C. parent parent parent parentparent parent parent parent

TABLE 2 (1/4) Component Ex. 9 Ex. 10 Ex. 11 Ex. 12 Ex. 13 Ex. 14 Ex. 15Ex. 16 Ex. 17 Ethyl 75.0 80.0 80.0  82.0  84.0  80.0 84.0  80.0  80.0eicosapentaenoate Purified water  2.0  2.0 1.0 1.0 1.0  1.0 1.0 1.0  1.0Polyoxyethylene (20) — — — — 10.0  10.0 8.0 10.0  10.0 sorbitan oleateSorbitan —  7.5 5.0 5.0 4.0  4.0 4.0 4.0 — monolaurate Sorbitan — — — —— — — — — sesquioleate Sorbitan — — — — — — — —  4.0 monooleate Glyceryl— — — — — — — 1.0 — monooleate Decaglyceryl 15.0 — 9.0 7.0 8.0 — — — —oleate Polyoxyl 35  8.0 10.5 5.0 5.0 3.0  5.0 3.0 5.0  5.0 castor oilSoybean — — — — — — — — — lecithin Propylene — — — — — — — — — GlycolEthanol — — — — — — — — — Total 100.00 100.00 100.00  100.00  100.00 100.00 100.00  100.00  100.00 (2/4) Ex. 9 Ex. 10 Ex. 11 Ex. 12 Ex. 13Ex. 14 Ex. 15 Ex. 16 Ex. 17 Test Ex. 1 Appear- Trans- Trans- Trans-Trans- Trans- Trans- Trans- Trans- Trans- ance parent parent parentparent parent parent parent parent parent Test Ex. 2 Self- Good GoodGood Good Good Good Good Good Good emulsifying property Composition GoodGood Good Good Good Good Good Good Good dispersibility Emulsion GoodGood Good Good Good Good Good Good Good stability Test Ex. 3 37° C. 0.180.25 0.22 0.29 0.29 0.18 0.18 0.21 0.21 Emulsion Purified droplet water(μm) diameter 37° C. 0.18 0.34 0.22 0.25 0.26 0.29 0.17 0.22 0.27Japanese Pharmacopeia 1st liquid (μm) Test Ex. 4 Stored at Trans- Trans-Trans- Trans- Trans- Trans- Trans- Trans- Trans- Appearance 5° C. parentparent parent parent parent parent parent parent parent Stored at Trans-Trans- Trans- Trans- Trans- Trans- Trans- Trans- Trans- 40° C. parentparent parent parent parent parent parent parent parent (3/4) Comp.Comp. Comp. Comp. Comp. Component Ex. 4 Ex. 5 Ex. 6 Ex. 7 Ex. 8 Ethyl80.0 75.2  70.0 80.0 80.0 eicosapentaenoate Purified water — — — —  1.0Polyoxyethylene (20) — 5.8 — 11.4 — sorbitan oleate Sorbitan  7.5 — 14.3— — monolaurate Sorbitan — — —  8.6 — sesquioleate Sorbitan — — — — —monooleate Glyceryl — — — — — monooleate Decaglyceryl — — — — — oleatePolyoxyl 35 10.5 5.8 15.7 — 19.0 castor oil Soybean — 6.5 — — — lecithinPropylene — 6.7 — — — Glycol Ethanol  2.0 — — — — Total 100.00 100.00 100.00 100.00 100.00 (4/4) Comp. Comp. Comp. Comp. Comp. Ex. 4 Ex. 5 Ex.6 Ex. 7 Ex. 8 Test Ex. 1 Appear- Separ- Trans- Trans- Trans- Separ- anceated parent parent parent ated Test Ex. 2 Self- Not Good Good Good Notemulsifying evaluated evaluated property Composition Good Good Gooddispersibility Emulsion Good Good Good stability Test Ex. 3 37° C. 0.180.17 0.68 Emulsion Purified droplet water (μm) diameter 37° C. 0.18 0.480.33 Japanese Pharmacopeia 1st liquid (μm) Test Ex. 4 Stored at Trans-Precip- Separ- Appearance 5° C. parent itated ated Stored at Separ-Trans- Separ- 40° C. ated parent ated

The composition of Example 1 contained a polyoxyethylene sorbitan fattyacid ester as the only emulsifier together with a specified amount ofwater, and, as shown in Table 1, had good appearance and excellentproperties including self-emulsifying property. This result indicatesthat the merits of the present invention are realized even by acomposition only containing a polyoxyethylene sorbitan fatty acid esteras an emulsifier.

The compositions of Examples 2 through 8 and 14 through 17 had variousemulsifiers added thereto apart from the polyoxyethylene sorbitan fattyacid ester as an emulsifier, and further contained water. Thecompositions were excellent in appearance, self-emulsifying property andother properties, as was the case with the composition of Example 1.

The compositions of Examples 7 and 8 as well as Comparative Examples 1and 2 contained water in varied amounts. The composition of ComparativeExample 1 contained no water, and became separated. The composition ofComparative Example 2, which contained 8% by weight of water, alsobecame separated.

In the present invention, water is used instead of ethanol or apolyhydric alcohol in order to improve the compatibility of acomposition. The composition having contained no water was separated dueto its inadequate compatibility. At the same time, the composition withtoo high a water content was also separated. Separation did not occur inthe compositions of Examples 1 through 9 each having contained 0.5 to 4%by weight of water. These results indicate that addition of water in aspecified amount of about 0.5% to about 6% by weight is important inpreparing the inventive composition which is excellent in appearance andproperties.

The composition of Comparative Example 3, which contained water and hada high ethyl eicosapentaenoate content of 94% by weight, becameseparated. It is considered that even a composition containing thespecified amount of water will be separated if it has an oil contenthigher than 70 to 90% by weight because the amount of emulsifierscontainable is reduced relative to the amount of oil components.

The composition of Comparative Example 4 contained no water but ethanol,and separation was observed in its appearance evaluation.

The composition of Example 10 was prepared by replacing the ethanol asused in Comparative Example 4 by water, and was good in appearance. Itis considered that, in the case of water, a content of about 2% byweight can bring about an adequate compatibility, while separationoccurred in the composition of Comparative Example 4 having contained 2%by weight of ethanol due to the shortage of ethanol.

The composition of Comparative Example 5 contained no water but lecithinand a polyhydric alcohol. As in the case of Example 1 and the like, thiscomposition had good appearance and excellent properties includingself-emulsifying property at room temperature.

The composition, however, was separated after overnight storage at 40°C., which demonstrates that addition of the specified amount of waterallows a composition of good appearance even in the environment athigher or lower temperatures.

The compositions of Examples 9 through 13 each contained at least twoemulsifiers selected from among a sorbitan fatty acid ester, a glycerinfatty acid ester and a polyoxyl castor oil, and further contained water.As shown in Table 2, the compositions had good appearance and wereexcellent in self-emulsifying property and other properties.

On the other hand, the composition of Comparative Example 8, whichcontained only one selected from among the above emulsifiers, had aseparated appearance. The results indicate that two or more emulsifiersneed to be selected.

The compositions of Comparative Examples 5 through 7 each containedemulsifiers selected from among a polyoxyethylene sorbitan fatty acidester, a sorbitan fatty acid ester and a polyoxyl castor oil, andcontained no water. Although the compositions were transparent inappearance at room temperature, separation or precipitation occurred inthe compositions during the storage at lower and/or higher temperaturesbecause of their not containing water.

The composition of Comparative Example 8 only contained a polyoxylcastor oil as an emulsifier, and became separated at temperatures of 5°C. and 40° C. In the present invention, in order to obtain theself-emulsifying composition which has good performance if containingthe specified amount of water, it is necessary to use, as an emulsifyingagent, i) a polyoxyethylene sorbitan fatty acid ester or ii) at leasttwo emulsifiers selected from among a sorbitan fatty acid ester, aglycerin fatty acid ester and a polyoxyethylene castor oil. It is seenfrom this Comparative Example that the use of a polyoxyethylene castoroil alone does not allow the self-emulsifying composition as expected.In other words, it has been found that a certain emulsifier oremulsifying agent needs to be used for the self-emulsifying compositionwhich has good performance if containing the specified amount of water.

Test Example 5 <Pharmacokinetics in Beagles>

The composition of Example 14 was orally administered to 6 male beagles(at the age of 2 to 6 years with the body weight of 13 kg, 3 Marshallbeagles and 3 Nosan beagles) under fasting conditions, and blood EPAconcentration was evaluated. The test animals had been fasted since 18hours or more before the administration, and each animal wasadministered with the composition in an amount corresponding to 600 mgof the EPA-E. Blood was collected before the administration, and 0.5, 1,1.5, 2, 3, 4, 6, 8, and 24 hours after the administration, and plasmawas separated to measure plasma EPA concentration by LC/MS/MS (method inwhich a sample is isolated by liquid chromatography, then subjected tomass spectrometry to conduct separation and measurement thereon). Thecontrol group was administered with the EPA-E stock solutionencapsulated in a capsule.

Table 3 shows the maximum blood concentration (Cmax), the area under theblood concentration vs time curve from zero to two hours (AUC₀₋₂) andthe area under the blood concentration vs time curve from zero to 24hours (AUC₀₋₂₄) as calculated from the test results. In the calculationof each parameter, correction was made by subtracting the blood EPAconcentration before the administration from the measured bloodconcentration.

TABLE 3 Ex. 14 EPA-E Stock solution Results of Test Ex. 5 (Fasted)(Control fasted) Cmax (μg/mL) 120.7 16.6 AUC₀₋₂ (μg/mL · hr) 84.0 14.4AUC₀₋₂₄ (μg/mL · hr) 844.6 188

In the animals as administered with the self-emulsifying composition ofExample 14, values of the Cmax and the AUC₀₋₂, which are parameters ofthe absorption speed, were higher than the control group (fasted). Withrespect to the AUC₀₋₂ which is in particular a parameter of the bloodconcentration increase immediately after the administration, the valuesin the animals as administered with the composition of Example 14 wereabout six times as high as those in the control group. The Cmax valueswere about 7.3 times as high as those in the control group. On the otherhand, with respect to the AUC₀₋₂₄ as a parameter of the absorptionamount, the values in the animals as administered with theself-emulsifying composition of Example 14 were about 4.5 times as highas those in the control group. More specifically, it was confirmed that,when the self-emulsifying composition of Example 14 was administered,amount of the EPA absorbed until 24 hours after the oral administrationincreased, and also, EPA absorption was rapid especially after the oraladministration compared to the control group. Accordingly, theself-emulsifying composition of the present invention would be acandidate for the self-emulsifying preparation capable of rapidly andmarkedly increasing the blood EPA concentration with rapid and effectivepharmacological action even if taken under pre-meal, pre-sleeping, orother fasting conditions.

Test Example 6 <Pharmacokinetics in Crab-Eating Macaques>

The composition of Example 14 is orally administered to 6 crab-eatingmacaques (at the age of 2 to 5 years with the body weight of 2.70 to4.65 kg; Hamuri) under fasting conditions, and blood EPA concentrationis evaluated. The test animals are fasted for 12 hours or more beforethe administration, and each animal is administered with theself-emulsifying composition in an amount corresponding to 45 mg/kg bodyweight of the EPA-E. The control group is administered with the EPA-Estock solution encapsulated in a capsule. Blood is collected before theadministration, and 1, 2, 4, 6, 8, 10, 12, 24, 48 and 72 hours after theadministration, and plasma is separated to measure EPA in plasma byLC/MS/MS. From the test results, the maximum blood concentration (Cmax),the area under the blood concentration vs time curve from zero to 12hours (AUC₀₋₁₂), and the area under the blood concentration vs timecurve from zero to 72 hours (AUC₀₋₇₂) are calculated. In the calculationof each parameter, correction is made by subtracting the blood EPAconcentration before the administration from the measured bloodconcentration.

In the animals having the composition of Example 14 administeredthereto, values of blood concentration parameters, such as the Cmax andthe AUC₀₋₁₂, are increased as compared with the control group. Morespecifically, it is confirmed that, when the self-emulsifyingcomposition of Example 14 is administered, amount of the EPA absorbed isincreased, and also, EPA absorption is rapid after the oraladministration.

(Example 2-1) Self-Emulsifying Capsule Preparation.

A soft gelatin capsule filled with 375 mg (amount corresponding to 300mg of EPA-E) of the self-emulsifying composition as obtained in Example14 was produced by rotary method. The self-emulsifying capsulepreparation thus produced was identical in shape to the soft gelatincapsule as filled with EPA-E alone, and escaped from such disadvantagesas the deformation of capsule film immediately after the production.

(Referential Example 2-2 and Comparative Example 2-3) CapsulePreparations.

The self-emulsifying composition of the Example and the composition ofthe Comparative Example were prepared and stored by repeating the methodof Example 1 so that the compositional ratios were as shown in Table 4.Formulations of the compositions are shown in Table 4.

A soft gelatin capsule filled with 375 mg of the composition ofReferential Example 2-1 and that filled with 441 mg of the compositionof Comparative Example 2-2 (both amounts corresponding to 300 mg ofEPA-E) were produced by rotary method. The self-emulsifying capsulepreparation thus produced was identical in shape to the soft gelatincapsule as filled with EPA-E alone, and escaped from such disadvantagesas the deformation of capsule film.

Test Example 6 <Capsule Hardness Retention>

The capsule preparations of Example 2-1, Referential Example 2-2 andComparative Example 2-3 were measured in hardness. Each preparation wasalso measured in hardness after the storage at 40° C. and a relativehumidity of 75% for one, two, and four weeks.

The results at the initial stage and the results after the storage at40° C. for one, two, and four weeks are shown in Table 4. Thepreparation at the initial stage refers to the preparation which hasbeen stored at room temperature after its production until theevaluation of the hardness. Since having been stored at 40° C. as sealedin aluminum packages, the preparations were not affected by themoisture.

TABLE 4 Referential Comparative Component Ex. 2-1 Ex. 2-2 Ex. 2-3 Ethyleicosapentaenoate 80.0 80.0  68.0  Purified water 1.0 2.0 —Polyoxyethylene (20) 10.0 5.8 7.1 sorbitan oleate Sorbitan monolaurate4.0 — — Polyoxyl 35 castor oil 5.0 5.8 7.1 Soybean lecithin — 6.4 9.5Propylene glycol — — 8.3 Total 100.0 100.0  100.0  Test Ex. 6 Initial31.8 28.9  15.7  Hardness stage (kgf) At 40° C. — — 9.1 for 1 week At40° C. 31.1 — 8.9 for 2 weeks At 40° C. 30.8 27.4  8.1 for 4 weeks

The preparation of Example 2-1 is a capsule preparation of the presentinvention, and the preparation of Referential Example 2-2 is of aformulation replacing sorbitan monolaurate contained in Example 2-1 bysoybean lecithin. The preparations had hardness values of 31.8 kgf and28.9 kgf, respectively, at the initial stage, values very close to eachother, and such values were essentially not reduced even after thestorage at 40° C. for one to four weeks. This indicates that neither asorbitan fatty acid ester nor soybean lecithin is a component causingthe reduction in hardness of a capsule.

The preparation of Comparative Example 2-3 is of a formulation replacingwater in Referential Example 2-2 by propylene glycol. The hardness ofthis preparation was about 54% of that of Referential Example 2-2, thatis to say, the preparation was inferior in hardness already at theinitial stage. Moreover, the hardness of the preparation was greatlyreduced after the storage at 40° C. for only one week.

It was found from the above that, while a polyhydric alcohol possiblycomprising about 8% of the liquid content will cause the reduction inhardness, the inventive composition that contains no polyhydric alcoholsbut water does not cause the reduction in hardness.

INDUSTRIAL APPLICABILITY

The self-emulsifying composition of the present invention is excellentin at least one out of the compatibility (appearance), theself-emulsifying property, the composition dispersibility, the emulsionstability and the absorbability, and it, as being absorbed rapidly evenif taken before meals, suppresses increase of serum TG after the meal.The self-emulsifying composition of the present invention is useful forincorporating in various foods, or as food for special dietary uses,food with health claims (food for specified health use and food withnutrient function claims), health food (supplement), or a pharmaceuticalproduct.

The self-emulsifying composition of the present invention has no or lowcontent of the polyhydric alcohol, and therefore, the composition isfree from the problem of softening and deformation of the capsule duringthe distribution or storage caused by the polyhydric alcohol. In otherwords, the self-emulsifying composition of the present invention isassociated with reduced risk of quality change.

The self-emulsifying composition of the present invention has thequality as a pharmaceutical product capable of being stored in a cold orhot location since the composition does not become cloudy or separatedeven if stored in low or high temperature environment.

1. A self-emulsifying composition comprising, when the self-emulsifyingcomposition is defined to be 100% by weight as a whole: a) 70 to 90% byweight of at least one compound selected from the group consisting of ω3polyunsaturated fatty acids and their pharmaceutically acceptable saltsand esters, b) 0.5 to 6% by weight of water, c) 1 to 29% by weight of anemulsifying agent comprising i) a polyoxyethylene sorbitan fatty acidester or ii) at least two members selected from the group consisting ofa sorbitan fatty acid ester, a glycerin fatty acid ester and apolyoxyethylene castor oil; or 1 to 29% by weight of an emulsifyingagent comprising i) a polyoxyethylene sorbitan fatty acid ester and ii)at least one member selected from the group consisting of a sorbitanfatty acid ester, a glycerin fatty acid ester and a polyoxyethylenecastor oil, wherein d) a content of ethanol is up to 4% by weight, e) acontent of polyhydric alcohol is up to 4% by weight, and f) a content oflecithin is lower than 2.1% by weight, wherein the self-emulsifyingcomposition has a non-separated or non-cloudy appearance and has atransparent appearance when stored in the environment of 5° C. or 40° C.for 12 hours.
 2. The self-emulsifying composition according to claim 1,wherein a content of lecithin in the composition is 0 parts by weight inrelation to 100 parts by weight of the at least one compound selectedfrom the group consisting of ω3 polyunsaturated fatty acids and theirpharmaceutically acceptable salts and esters.
 3. The self-emulsifyingcomposition according to claim 1, wherein the ω3 polyunsaturated fattyacids and their pharmaceutically acceptable salts and esters comprise atleast one member selected from the group consisting of eicosapentaenoicacid (EPA), docosahexaenoic acid (DHA), and their pharmaceuticallyacceptable salts and esters.
 4. The self-emulsifying compositionaccording to claim 1, wherein the polyhydric alcohol is propylene glycolor glycerin.
 5. The self-emulsifying composition according to claim 1,wherein the content of the polyhydric alcohol is up to 1% by weight ofthe composition.
 6. The self-emulsifying composition according to claim1, wherein the content of the ethanol is up to 1% by weight of thecomposition.
 7. The self-emulsifying composition according to claim 1,wherein the mean droplet diameter when the composition is dispersed inwater is up to 2 μm.
 8. A capsulated self-emulsifying preparationcomprising a capsule which comprises a liquid self-emulsifyingcomposition, with the self-emulsifying composition comprising, when theself-emulsifying composition is defined to be 100% by weight as a whole:a) 70 to 90% by weight of at least one compound selected from the groupconsisting of ω3 polyunsaturated fatty acids and their pharmaceuticallyacceptable salts and esters, b) 0.5 to 6% by weight of water, c) 1 to29% by weight of an emulsifying agent comprising i) a polyoxyethylenesorbitan fatty acid ester or ii) at least two members selected from thegroup consisting of a sorbitan fatty acid ester, a glycerin fatty acidester and a polyoxyethylene castor oil; or 1 to 29% by weight of anemulsifying agent comprising i) a polyoxyethylene sorbitan fatty acidester and ii) at least one member selected from the group consisting ofa sorbitan fatty acid ester, a glycerin fatty acid ester and apolyoxyethylene castor oil, d) an ethanol content which is up to 4% byweight of the composition, and e) a polyhydric alcohol content which isup to 4% by weight of the composition, wherein the composition comprisesessentially no lecithin, and f) a content of lecithin is lower than 2.1%by weight of the composition, wherein the self-emulsifying compositionhas a non-separated or non-cloudy appearance and has a transparentappearance when stored in the environment of 5° C. or 40° C. for 12hours, and wherein the capsule is a hard capsule or a soft capsule. 9.The capsulated self-emulsifying preparation according to claim 8,wherein the capsule is a soft capsule and a capsule film of the softcapsule comprises gelatin.
 10. The capsulated self-emulsifyingpreparation according to claim 8, wherein a content of lecithin in theself-emulsifying composition is 0 parts by weight in relation to 100parts by weight of the at least one compound selected from the groupconsisting of ω3 polyunsaturated fatty acids and their pharmaceuticallyacceptable salts and esters.
 11. The capsulated self-emulsifyingpreparation according to claim 8, wherein the ω3 polyunsaturated fattyacids and their pharmaceutically acceptable salts and esters comprise atleast one member selected from the group consisting of eicosapentaenoicacid (EPA), docosahexaenoic acid (DHA), and their pharmaceuticallyacceptable salts and esters.
 12. The capsulated self-emulsifyingpreparation according to claim 8, wherein the polyhydric alcohol ispropylene glycol or glycerin.
 13. The capsulated self-emulsifyingpreparation according to claim 8, wherein the content of the polyhydricalcohol is up to 1% by weight of the composition.
 14. The capsulatedself-emulsifying preparation according to claim 8, wherein the contentof the ethanol is up to 1% by weight of the composition.